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Transcription factors play vital roles in neuron development; however, little is known about the role of these proteins in maintaining neuronal homeostasis. Here, we show that the transcription factor RREB1 (Ras-responsive element-binding protein 1) is essential for neuron survival in the mammalian brain. A spontaneous mouse mutation causing loss of a nervous system-enriched Rreb1 transcript is associated with progressive loss of cerebellar Purkinje cells and ataxia. Analysis of chromatin immunoprecipitation and sequencing, along with RNA sequencing data revealed dysregulation of RREB1 targets associated with the microtubule cytoskeleton. In agreement with the known role of microtubules in dendritic development, dendritic complexity was disrupted in Rreb1-deficient neurons. Analysis of sequencing data also suggested that RREB1 plays a role in the endomembrane system. Mutant Purkinje cells had fewer numbers of autophagosomes and lysosomes and contained P62- and ubiquitin-positive inclusions. Together, these studies demonstrate that RREB1 functions to maintain the microtubule network and proteostasis in mammalian neurons.

Under stress, Purkinje cells (PCs) undergo a variety of reactive morphological changes. These can include swellings of neuronal processes. While axonal swellings, "torpedoes", have been well-studied, dendritic swellings (DS) have not been the centerpiece of study. Surprisingly little is known about their frequency or relationship to other morphological changes in degenerating PCs. Leveraging a large brain bank, we (1) examined the morphology of DS, (2) quantified DS, and (2) examined correlations between counts of DS versus 16 other PC morphological changes in a broad range of cerebellar degenerative disorders. There were 159 brains − 100 essential tremor (ET), 13 Friedreich's ataxia, and 46 spinocerebellar ataxia (SCA) (14 SCA1, 7 SCA2, 13 SCA3, 5 SCA6, 5 SCA7, and 2 SCA8). DS were a feature of PCs across all these disorders, with varying morphologies and changes elsewhere in the dendritic arbor. On Luxol fast blue/hematoxylin and eosin-stained sections, the median number of DS per PC ranged from 0.001 in ET to 0.025 in SCA8. Bielschowsky-stained sections yielded higher counts, from 0.003 in ET to 0.042 in SCA6. Torpedo counts exceeded DS counts by one order of magnitude. DS counts were more robustly correlated with torpedo counts than with counts for any of the other PC morphological changes. In summary, DS ranged in prevalence across cerebellar degenerative disorders, from 1/1,000 to 42/1,000 PCs. Across disorders of cerebellar degeneration, these swellings of the dendritic compartment were most robustly correlated with swellings of the axonal compartment, suggesting a similar type of cellular response to duress. [ABSTRACT FROM AUTHOR]

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses plays an important role in cerebellum-related motor coordination and learning. LTD is induced by the conjunction of PF stimulation and climbing fiber (CF) stimulation or somatic PC depolarization, while long-term potentiation (LTP) is induced by PF stimulation alone. Therefore, it is considered that different types of stimulation induce different types of synaptic plasticity. However, we found that a small number of conjunctive stimulations (PF + somatic depolarization of PC) induced LTP, but did not induce LTD of a small size. This LTP was not associated with changes in paired-pulse ratio, suggesting postsynaptic origin. Additionally this LTP was dependent on nitric oxide. This LTP was also induced by a smaller number of physiological conjunctive PF and CF stimuli. These results suggested that a larger number or longer period of conjunctive stimulation is required to induce LTD by overcoming LTP. Ca2+ transients at the PC dendritic region was measured by calcium imaging during LTD-inducing conjunctive stimulation. Peak amplitude of Ca2+ transients increased gradually during repetitive conjunctive stimulation. Instantaneous peak amplitude was not different between the early phase and late phase, but the average amplitude was larger in the later phase than in the early phase. These results show that LTD overcomes LTP, and increased Ca2+ integration or a number of stimulations is required for LTD induction. [ABSTRACT FROM AUTHOR]

Key points Cerebellar damage early in life often causes long‐lasting motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher‐order control of all behaviours. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is a major direct target of the cerebellar nuclei, conveying cerebellar signals to the cerebral cortex. Despite its crucial position in cerebello–cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole‐cell patch‐clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The ablation of Purkinje cells in the developing cerebellum strengthened cerebellothalamic synapses and enhanced thalamic suprathreshold activities. Purkinje‐cell specific deletion of tuberous sclerosis complex subunit 1 (Tsc1), an autism‐associated gene for which the protein product negatively regulates the mammalian target of rapamycin, also strengthened cerebellothalamic synapses. However, this strengthening occurred only in homozygous deletion, whereas both homozygous and hemizygous deletion are known to cause autism‐like behaviours. These results suggest that, although the cerebellothalamic projection is vulnerable to disturbances in the developing cerebellar cortex, other changes may also drive the behavioural consequences of early cerebellar perturbation. Cerebellar damage early in life often causes motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. Recent studies focus on how the developing cerebellum affects the formation and function of the cerebral cortex, the higher‐order centre for all behaviours. However, the cerebellum does not directly connect to the cerebral cortex. Here, we studied the consequences of early cerebellar perturbation on the thalamus because it is a direct postsynaptic target of the cerebellum, sending cerebellar signals to the cerebral cortex. Loss of cerebellar Purkinje cells, which are commonly associated with various neurological disorders, strengthened cerebellothalamic synapses, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum. Purkinje cell‐specific loss of tuberous sclerosis complex‐1, a negative regulator of mammalian target of rapamycin, is an established mouse model of autism. This mouse model also showed strengthened cerebellothalamic synapses. [ABSTRACT FROM AUTHOR]

Patients with Duchenne muscular dystrophy (DMD) commonly show specific cognitive deficits in addition to a severe muscle impairment caused by the absence of dystrophin expression in skeletal muscle. These cognitive deficits have been related to the absence of dystrophin in specific regions of the central nervous system, notably cerebellar Purkinje cells (PCs). Dystrophin has recently been involved in GABAA receptors clustering at postsynaptic densities, and its absence, by disrupting this clustering, leads to decreased inhibitory input to PC. We performed an in vivo electrophysiological study of the dystrophin‐deficient muscular dystrophy X‐linked (mdx) mouse model of DMD to compare PC firing and local field potential (LFP) in alert mdx and control C57Bl/10 mice. We found that the absence of dystrophin is associated with altered PC firing and the emergence of fast (~160–200 Hz) LFP oscillations in the cerebellar cortex of alert mdx mice. These abnormalities were not related to the disrupted expression of calcium‐binding proteins in cerebellar PC. We also demonstrate that cerebellar long‐term depression is altered in alert mdx mice. Finally, mdx mice displayed a force weakness, mild impairment of motor coordination and balance during behavioural tests. These findings demonstrate the existence of cerebellar dysfunction in mdx mice. A similar cerebellar dysfunction may contribute to the cognitive deficits observed in patients with DMD. [ABSTRACT FROM AUTHOR]

Background: Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2. Methods: Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis. Results: Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death. Conclusion: In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • TNAP deficiency causes developmental delays and impairs sensorimotor function. • TNAP deficiency downregulates transcription factors Neurog2 and RORα. • TNAP deficiency downregulates glutamate transporter EAAT4. • TNAP deficiency upregulates death markers PMAIP1, IGFBP-3 and Fas. • TNAP deficiency results in abnormal Purkinje cell morphology. Loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene can result in hypophosphatasia (HPP), an inherited multi-systemic metabolic disorder that is well-known for skeletal and dental hypomineralization. However, emerging evidence shows that both adult and pediatric patients with HPP suffer from cognitive deficits, higher measures of depression and anxiety, and impaired sensorimotor skills. The cerebellum plays an important role in sensorimotor coordination, cognition, and emotion. To date, the impact of TNAP mutation on the cerebellar circuitry development and function remains poorly understood. The main objective of this study was to investigate the roles of TNAP in cerebellar development and function, with a particular focus on Purkinje cells, in a mouse model of infantile HPP. Male and female wild type (WT) and TNAP knockout (KO) mice underwent behavioral testing on postnatal day 13–14 and were euthanized after completion of behavioral tests. Cerebellar tissues were harvested for gene expression and immunohistochemistry analyses. We found that TNAP mutation resulted in significantly reduced body weight, shorter body length, and impaired sensorimotor functions in both male and female KO mice. These developmental and behavioral deficits were accompanied by abnormal Purkinje cell morphology and dysregulation of genes that regulates synaptic transmission, cellular growth, proliferation, and death. In conclusion, inactivation of TNAP via gene deletion causes developmental delays, sensorimotor impairment, and Purkinje cell maldevelopment. These results shed light on a new perspective of cerebellar dysfunction in HPP. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion The role of propionic acid (PPA) in eliciting behaviors analogous to autism in rat models is a documented phenomenon. This study examines the therapeutic implications of pentoxifylline—an agent traditionally used for peripheral vascular diseases—on these autism‐like behaviors by modulating brain proteins and reducing pro‐inflammatory cytokines like tumor necrosis factor‐α (TNF‐α) in a rat model.This research involved 30 male Wistar albino rats, which were divided into three distinct groups: a baseline control set, a PPA‐treated cluster receiving a 250 mg/kg/day dose of PPA via intraperitoneal injection for a span of five days followed by saline orally, and a PPA group administered an oral dose of pentoxifylline at 300 mg/kg/day over 15 days. Subsequent to the treatment phase, euthanasia was carried out for the extraction of brain and blood samples, which were then analyzed for histopathological and biochemical markers.The pentoxifylline‐treated subjects demonstrated a significant mitigation in the manifestation of autistic‐like behaviors, as assessed through a triad of social interaction tests. A noteworthy decline in TNF‐α levels was observed, alongside a significant rise in the concentration of adenosine triphosphate and nerve growth factor in brain tissue (p < 0.05). Histopathological analysis underscored a reduction in oxidative stress and a significant preservation of neuronal cell types, specifically pyramidal neurons in the hippocampal CA1 and CA3 regions and Purkinje cells in the cerebellum (p < 0.001).Pentoxifylline treatment has been found to effectively reduce the behavioral symptoms associated with autism, as well as biochemical and histopathological disruptions induced by PPA in rat models, highlighting its potential as a neurotherapeutic agent. [ABSTRACT FROM AUTHOR]

Uremic Encephalopathy results from the elevation of toxins and blood-brain barrier (BBB) disruption. Renal Ischemia/Reperfusion (I/R) injury is the principal cause of acute kidney injury and brain tissue injury. The present study was crafted to estimate the restorative impact of platelet-rich plasma (PRP) and exosome injection before the reperfusion phase on the kidney following renal I/R injury and its influence on brain tissue by tracking the histopathological, biochemical, and Doppler ultrasonography alternations in both kidney and brain tissue. Forty mature male rats were divided into five groups as follows: control, I/R, PRP, exosome, and Exosome + PRP. Renal Doppler ultrasonography was traced for all rats. Serum kidney functions and acetylcholine esterase enzyme (AchE) were evaluated. Both Gamma-aminobutyric acid (GABA) and glutamate were assessed in brain tissues. The oxidative stress (malondialdehyde), anti-oxidative (glutathione and catalase), and pro-inflammatory (Tumor necrosis factor- α and interleukin-6) markers were estimated in renal tissues. Additionally, morphometric histological examination was performed in both renal and brain tissues. Both PRP and exosome-received rats exhibited a significant improvement in both serum kidney functions and AchE compared to I/R rats. There was a 3.39-fold increase in GABA and a 2.27-fold decrease in glutamate levels in the brain tissue of PRP rats compared to the I/R rats. A significant elevation (P ≤ 0.0001) of glutathione and catalase besides a significant reduction in the expression of TNF-α and IL-6 was observed in renal tissue compared to I/R rats. A significant severe reduction (P < 0.0001) in the number of Purkinje cells, pyramidal cells in the cerebellar cortex, and the CA1 region in the hippocampus was observed in I/R rats which was significantly alleviated by both PRP and exosome. Furthermore, there was a significant improvement in Doppler parameters. PRP exerted a significant superior impact on the restoration of kidney functions and repairing uremic-induced damage in brain tissue. [ABSTRACT FROM AUTHOR]

Two‐photon high‐speed fluorescence calcium imaging stands as a mainstream technique in neuroscience for capturing neural activities with high spatiotemporal resolution. However, challenges arise from the inherent tradeoff between acquisition speed and image quality, grappling with a low signal‐to‐noise ratio (SNR) due to limited signal photon flux. Here, a contrast‐enhanced video‐rate volumetric system, integrating a tunable acoustic gradient (TAG) lens‐based high‐speed microscopy with a TAG‐SPARK denoising algorithm is demonstrated. The former facilitates high‐speed dense z‐sampling at sub‐micrometer‐scale intervals, allowing the latter to exploit the spatial redundancy of z‐slices for self‐supervised model training. This spatial redundancy‐based approach, tailored for 4D (xyzt) dataset, not only achieves >700% SNR enhancement but also retains fast‐spiking functional profiles of neuronal activities. High‐speed plus high‐quality images are exemplified by in vivo Purkinje cells calcium observation, revealing intriguing dendritic‐to‐somatic signal convolution, i.e., similar dendritic signals lead to reverse somatic responses. This tailored technique allows for capturing neuronal activities with high SNR, thus advancing the fundamental comprehension of neuronal transduction pathways within 3D neuronal architecture. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias. Editor's summary: Spinocerebellar ataxias (SCAs) are neurodegenerative diseases affecting coordination and movement. Purkinje cells (PCs) are especially vulnerable in SCAs, but their low abundance makes cell type–specific transcriptomic profiling difficult. Using a PC enrichment protocol for snRNA-seq, Bartelt et al. discovered that genes contributing to zebrin-II PC subtype identity were dysregulated in the SCA7-266Q mouse model. Immunohistochemistry revealed a loss of zebrin-II striping in the cerebella of SCA7-266Q mice and mouse models of other SCA subtypes. snRNA-seq on postmortem cerebellar tissue from patients with SCA7 demonstrated zebrin-II dysregulation in molecular layer interneurons. These results suggest that dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across SCAs. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

The prevailing belief has been that the fundamental structures of cerebellar neuronal circuits, consisting of a few major neuron types, are simple and well understood. Given that the cerebellum has long been known to be crucial for motor behaviors, these simple yet organized circuit structures seemed beneficial for theoretical studies proposing neural mechanisms underlying cerebellar motor functions and learning. On the other hand, experimental studies using advanced techniques have revealed numerous structural properties that were not traditionally defined. These include subdivided neuronal types and their circuit structures, feedback pathways from output Purkinje cells, and the multidimensional organization of neuronal interactions. With the recent recognition of the cerebellar involvement in non-motor functions, it is possible that these newly identified structural properties, which are potentially capable of generating greater complexity than previously recognized, are associated with increased information capacity. This, in turn, could contribute to the wide range of cerebellar functions. However, it remains largely unknown how such structural properties contribute to cerebellar neural computations through the regulation of neuronal activity or synaptic transmissions. To promote further research into cerebellar circuit structures and their functional significance, we aim to summarize the newly identified structural properties of the cerebellar cortex and discuss future research directions concerning cerebellar circuit structures and their potential functions. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the relationship between demyelination and cellular reactions in the cerebellum of Canine Distemper Virus (CDV)-infected dogs. We subdivided the disease staging by adding the degree of demyelination determined by Luxol Fast Blue staining to the previously reported disease staging from the acute stage to the chronic stage, and investigated the relationship between demyelination in the cerebellum and the number and histological changes in astroglia, microglia, and Purkinje cells in each stage. Reactions of astrocytes and microglia were observed at an early stage when demyelination was not evident. Changes progressed with demyelination. Demyelination initially began in the medulla adjoining the fourth ventricle and gradually spread to the entire cerebellum, including the lobes. CDV immune-positive granules were seen from the early stage, and inclusion bodies also appeared at the same time. CDV immune-positive reaction and inclusion bodies were observed in astrocytes, microglia, neurons, ependymal cells, and even leptomeningeal mononuclear cells. On the other hand, infiltration of CDV-immunoreactive particles from the pia mater to the gray matter and further into the white matter through the granular layer was observed from an early stage. Purkinje cells decreased from the intermediate stage, and a decrease in cells in the granular layer was also observed. There was no clear association between age and each stage, and the stages did not progress with age. [ABSTRACT FROM AUTHOR]

Depression is a persistent illness affecting health, behavior, and performance in life. Worldwide morbidity and mortality are caused by depression. The current study intended to explore fumaric acid's potential protective effect against ciprofloxacin-provoked depression in rats and to determine its mechanism of action by studying its antioxidant and anti-inflammatory properties. Five groups of male Wistar albino rats (120 g ± 20) were employed; the first group received physiological saline, the second group received fumaric acid (80 mg/kg/day; orally) for 3 weeks, the third group was administered ciprofloxacin (50 mg/kg/day; orally) for 3 weeks to induce depression, the fourth group received a daily low dose of fumaric acid (40 mg/kg; orally) concurrent with ciprofloxacin and the fifth group received a daily high dose of fumaric acid (80 mg/kg; orally) concurrent with ciprofloxacin for 21 days. Then, behavior tests, oxidative stress indicators, inflammatory biomarkers, neurotransmitters, p190 Rho GTP, and histopathological examination were evaluated. Ciprofloxacin significantly increased oxidative stress biomarkers [malondialdehyde (MDA) as a lipid peroxidation marker and nitric oxide (NO)] and biomarkers of inflammation [Toll-like receptor4 (TLR-4)] and tumor necrosis factor-alpha (TNF-α) with reduction in the activities of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and catalase as well as brain contents of neurotransmitters and P190-RHO GTP. In addition, it causes necrosis of neurons and mild loss of Purkinje cells. Fumaric acid eliminates these effects of ciprofloxacin. Fumaric acid has beneficial effects as an anti-depressant in Wistar albino male rats that received ciprofloxacin. [ABSTRACT FROM AUTHOR]

Introduction: According to the neuroinflammatory hypothesis, a cytokine-mediated host innate immune response may be involved in the mechanisms that contribute to the process of neurodegeneration. Specifically, regarding prion diseases, some experimental murine models have evidenced an altered profile of inflammatory intermediaries. However, the local inflammatory response has rarely been assessed, and never in tissues from different natural models throughout the progression of neurodegeneration. Methods: The aim of this study was to use immunohistochemistry (IHC) to in situ assess the temporal protein expression of several cytokines in the cerebellum of sheep suffering from various clinical stages of scrapie. Results and discussion: Clear changes in the expression of most of the assessed markers were observed in the affected sheep compared to the healthy control sheep, and from different stages. In summary, this preliminary IHC study focusing in the Purkinje cell layer changes demonstrate that all cytokines or respective receptors studied (IL-1, IL-1R, IL-2R, IL-6, IL-10R, and TNFαR) except for IFNγR are disease-associated signaling proteins showing an increase or decrease in relation to the progression of clinical disease. In the future, this study will be extended to other inflammatory mediators and brain regions, focusing in particular on the release of these inflammatory mediators by astroglial and microglial populations. [ABSTRACT FROM AUTHOR]

Nasal respiratory disorders are linked to craniofacial anomalies and systemic dysfunctions. However, the implications of nasal respiratory disorders on brain development and their subsequent impact on brain functionalization remain largely unknown. Here, we describe that nasal obstruction from postnatal developmental stages in mice precipitates deficits in cerebellum-associated behaviors and compromised refinement and maturation of neural circuits in the cerebellum. We show that mice with nasal obstruction during developmental phases exhibit marked impairments in motor function and exhibit increased immobility time in forced swimming test. Additionally, we identified critical periods during which nasal respiration is essential for optimizing motor function and preserving mental health. Our study also reveals that nasal obstruction in mice disrupts the typical developmental process of synapse elimination in the cerebellum and hinders the normal transition of activity patterns in cerebellar Purkinje cell populations during development. Through comparing activity patterns in mouse models subjected to nasal obstruction at various stages, we suggest that the maturation of specific activity pattern among Purkinje cell populations is fundamental to the functional integrity of the cerebellum. Our findings highlight the indispensable role of adequate nasal respiration during development for the establishment and functional integrity of neural circuits, thereby significantly affecting brain function. Nasal obstruction during specific critical periods leads to motor deficits and depressive-like behaviors in mice, mediated by impaired synapse elimination and disrupted cerebellar activity patterns. [ABSTRACT FROM AUTHOR]

Spliceosomal GTPase elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) syndrome comprising cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these symptoms remains elusive. Here, we demonstrate that specific ablation of Eftud2 in cerebellar Purkinje cells (PCs) in mice results in severe ferroptosis, PC degeneration, dyskinesia, and cerebellar atrophy, which recapitulates phenotypes observed in patients with MFDM. Mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity, thereby suppressing PC ferroptosis. Importantly, we identified transcription factor Atf4 as a downstream target to regulate anti-ferroptosis effects in PCs in a p53-independent manner. Inhibiting ferroptosis efficiently rescued cerebellar deficits in Eftud2 cKO mice. Our data reveal an important role of Eftud2 in maintaining PC survival, showing that pharmacologically or genetically inhibiting ferroptosis may be a promising therapeutic strategy for EFTUD2 deficiency-induced disorders. [Display omitted] • Spliceosomal GTPase Eftud2 is essential for Purkinje cell development and survival • Eftud2 deficiency in PCs induces ferroptosis via a p53-independent manner • Eftud2 deficiency induces Scd1 and Gch1 downregulation through mis-splicing of Atf4 • Inhibition of ferroptosis efficiently rescues Eftud2 loss-induced PC death in vivo Alternative splicing critically regulates brain development. Yang et al. found that spliceosomal factor Eftud2 is essential for Purkinje cell (PC) development, survival, and cerebellar integrity by preventing ferroptosis. Inhibition of ferroptosis efficiently rescues PC death in Eftud2-deficient mice. These findings provide a promising therapeutic strategy for EFTUD2 deficiency-induced diseases. [ABSTRACT FROM AUTHOR]

Background Materials and methods Results Conclusion Global cerebral ischemia (GCI) leads to significant oxidative damage in the cerebellum, mainly affecting Purkinje cells. This study aimed to investigate the neuroprotective effects of berberine chloride (BBR), a compound known for its antioxidant properties against GCI.Fourty‐two adult male Wistar rats were divided into three groups: Sham, GCI, and GCI + BBR. Rats received BBR (50 mg/kg) seven days before and six hours after inducing GCI via bilateral common carotid artery occlusion for 20 min. They were assessed for locomotor activity by the open‐field test, the cerebellar biochemical factors malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), cerebellum volume and Purkinje neuron count by stereological analysis.The BBR treatment reduced the concentration of MDA and increased the activity of antioxidant enzymes SOD, CAT and GPx in the GCI + BBR group compared to the GCI group. Stereological analysis revealed higher Purkinje cell count, cerebellum, white matter, and gray matter volume in the GCI + BBR group compared to the GCI group. Furthermore, GCI + BBR showed enhanced locomotor function compared to the GCI group.BBR showed therapeutic benefits and improved locomotor function. It demonstrated antioxidative effects by lowering MDA levels, boosting enzymatic activities, and significantly mitigating Purkinje cell death and cerebellar volume loss. [ABSTRACT FROM AUTHOR]

Potassium channels stabilize the resting potential and neuronal excitability. Among them, erg (ether-à-go-go-related gene) K+ channels represent a subfamily of voltage-gated channels, consisting of erg1, erg2, and erg3 subunits; however, their subunit-specific neuronal functions in vivo are barely understood. To find erg3-and erg1-mediated functions, we generated global Kcnh7 (erg3) and conditional Kcnh2 (erg1) knockout mice. We found that erg3 channels stabilize the resting potential and dampen spontaneous activity in cerebellar Purkinje cells (PCs) and hippocampal CA1 neurons, whereas erg1 channels have suprathreshold functions. Lack of erg3 subunits induced hyperexcitability with increased action potential firing in PCs, but not in CA1 neurons. Notably, erg3 depletion caused depressive-like behavior with reduced locomotor activity, strongly decreased digging behavior, and shorter latencies to fall off a rotating wheel, while learning and memory remained unchanged. Our data show that erg K+ channels containing erg3 subunits mediate a neuronal subthreshold K+ current that plays important roles in the regulation of locomotor behavior in vivo. [ABSTRACT FROM AUTHOR]

We studied morphological features of the cerebellum in 14-day-old Wistar rats from reduced litters (the number of pups was reduced from 10-12 to 6 on the next day after birth). The control group comprised 14-day-old animals from litters of medium size (10-12 rat pups). Rats from reduced litters had greater body weight and brain weight. The weight of the cerebellum, together with the weight of the adjacent part of the brain stem and the thickness of cerebellar cortex also significantly exceeded the corresponding parameters in control animals. The thickness of the molecular layer of the cerebellar cortex and the numerical density of Purkinje cells in these rats did not differ significantly from the control. The thickness of the external granular (neurogenic) layer of the cerebellar cortex in rats from reduced litters was smaller. This can indicate accelerated reduction of this layer that persists in rats until days 20-22 of age. Numerical density of cells in the external granular layer of control and experimental animals was similar. Numerical density Ki-67+ cells in this layer, as well as GFAP+ glial cells in the granular layer of the cerebellar cortex in rats from reduced litters significantly exceeded the corresponding parameters in control animals. The cerebellum of rats from litters reduced 1 day after birth had a number of differences in important indicators reflecting the rate of its development during the neonatal and suckling periods of ontogeny. [ABSTRACT FROM AUTHOR]

Simple Summary: Physical overexertion surpassing the functional capacity of the nervous system causes the hyperactivation of the neural structures of the cerebellum. In turn, it causes the depletion of intracellular resources and progressive structural changes in cerebellar cells and fibers. After the forced swimming test, animals (n = 30) had significant morphological changes in pyriform cells, granule cells, internuncial neurons, and neuroglial cells. Pronounced degeneration of granular cells was observed, manifested by their fusion into conglomerates. These changes demonstrate that neurodegeneration in the cerebellum takes place in response to physical overexertion. Physical overexertion surpassing the functional capacity of the nervous system causes the hyperactivation of the neural structures of the cerebellum. In turn, it causes the depletion of intracellular resources and progressive structural changes in cerebellar cells and fibers. These degenerative changes may lead to cerebellar dysfunction, including the worsening of coordination, balance, and motor functions. In order to maintain the health and functioning of the cerebellum and the nervous system in general, one needs to avoid physical overexertion and have enough time to recover. Three major types of Purkinje cells were identified in control group animals. After the forced swimming test, animals had significant morphological changes in pyriform cells, granule cells, internuncial neurons, and neuroglial cells. In particular, the extreme degeneration of granule cells was manifested via their fusion into conglomerates. These changes demonstrate that neurodegeneration in the cerebellum takes place in response to physical overexertion. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant disease that arises from point mutations in the fatty acid elongase, Elongation of Very Long Chain Fatty Acids 4 (ELOVL4), which is essential for the synthesis of Very Long Chain-Saturated Fatty Acids (VLC-SFA) and Very Long Chain-Polyunsaturated Fatty Acids (VLC-PUFA) (28–34 carbons long). SCA34 is considered a neurodegenerative disease. However, a novel rat model of SCA34 (SCA34-KI rat) with knock-in of the W246G ELOVL4 mutation that causes human SCA34 shows early motor impairment and aberrant synaptic transmission and plasticity without overt neurodegeneration. ELOVL4 is expressed in neurogenic regions of the developing brain, is implicated in cell cycle regulation, and ELOVL4 mutations that cause neuroichthyosis lead to developmental brain malformation, suggesting that aberrant neuron generation due to ELOVL4 mutations might contribute to SCA34. To test whether W246G ELOVL4 altered neuronal generation or survival in the cerebellum, we compared the numbers of Purkinje cells, unipolar brush cells, molecular layer interneurons, granule and displaced granule cells in the cerebellum of wildtype, heterozygous, and homozygous SCA34-KI rats at four months of age, when motor impairment is already present. An unbiased, semi-automated method based on Cellpose 2.0 and ImageJ was used to quantify neuronal populations in cerebellar sections immunolabeled for known neuron-specific markers. Neuronal populations and cortical structure were unaffected by the W246G ELOVL4 mutation by four months of age, a time when synaptic and motor dysfunction are already present, suggesting that SCA34 pathology originates from synaptic dysfunction due to VLC-SFA deficiency, rather than aberrant neuronal production or neurodegeneration. [ABSTRACT FROM AUTHOR]

Climbing fibers, connecting the inferior olive and Purkinje cells, form the nervous system's strongest neural connection. These fibers activate after critical events like motor errors or anticipation of rewards, leading to bursts of excitatory postsynaptic potentials (EPSPs) in Purkinje cells. The number of EPSPs is a crucial variable when the brain is learning a new motor skill. Yet, we do not know what determines the number of EPSPs. Here, we measured the effect of nucleo-olivary stimulation on periorbital elicited climbing fiber responses through in-vivo intracellular Purkinje cell recordings in decerebrated ferrets. The results show that while nucleo-olivary stimulation decreased the probability of a response occurring at all, it did not reduce the number of EPSPs. The results suggest that nucleo-olivary stimulation does not influence the number of EPSPs in climbing fiber bursts. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) involve brain wide abnormalities that contribute to a constellation of symptoms including behavioral inflexibility, cognitive dysfunction, learning impairments, altered social interactions, and perceptive time difficulties. Although a single genetic variation does not cause ASD, genetic variations such as one involving a non-canonical Wnt signaling gene, Prickle2, has been found in individuals with ASD. Previous work looking into phenotypes of Prickle2 knock-out (Prickle2−/−) and heterozygous mice (Prickle2−/+) suggest patterns of behavior similar to individuals with ASD including altered social interaction and behavioral inflexibility. Growing evidence implicates the cerebellum in ASD. As Prickle2 is expressed in the cerebellum, this animal model presents a unique opportunity to investigate the cerebellar contribution to autism-like phenotypes. Here, we explore cerebellar structural and physiological abnormalities in animals with Prickle2 knockdown using immunohistochemistry, whole-cell patch clamp electrophysiology, and several cerebellar-associated motor and timing tasks, including interval timing and eyeblink conditioning. Histologically, Prickle2−/− mice have significantly more empty spaces or gaps between Purkinje cells in the posterior lobules and a decreased propensity for Purkinje cells to fire action potentials. These structural cerebellar abnormalities did not impair cerebellar-associated behaviors as eyeblink conditioning and interval timing remained intact. Therefore, although Prickle−/− mice show classic phenotypes of ASD, they do not recapitulate the involvement of the adult cerebellum and may not represent the pathophysiological heterogeneity of the disorder. [ABSTRACT FROM AUTHOR]

Autosomal recessive spinocerebellar ataxia 13 (SCAR13) is a neurological disease characterized by psychomotor delay, mild to profound intellectual disability with poor or absent language, nystagmus, stance ataxia, and, if walking is acquired, gait ataxia. Epilepsy and polyneuropathy have also been documented in some patients. Cerebellar atrophy and/or ventriculomegaly may be present on brain MRI. SCAR13 is caused by pathogenic variants in the GRM1 gene encoding the metabotropic receptor of glutamate type 1 (mGlur1), which is highly expressed in Purkinje cerebellar cells, where it plays a fundamental role in cerebellar development. Here we discuss the case of an 8-year-old patient who presented with a severe neurodevelopmental disorder with balance disturbance, absence of independent walking, absence of language, diffuse hypotonia, mild nystagmus, and mild dysphagia. Whole-exome sequencing revealed a compound heterozygosity for two likely pathogenic variants in the GRM1 gene, responsible for the patient's phenotype, and made it possible to diagnose autosomal recessive spinocerebellar ataxia SCAR13. The detected (novel) variants appear to be causative of a particularly severe picture with regard to neurodevelopment, in the context of the typical neurological signs of spinocerebellar ataxia. [ABSTRACT FROM AUTHOR]

Ovarian mature teratomas frequently contain central nervous system (CNS) tissue that often exhibits a variety of neuropathologic alterations. The author systematically examined the changes seen in CNS tissue from a series of 251 cases of resected ovarian mature teratomas. A total of 101 (40.2%) samples contained CNS tissue in varying amounts. The principal pathologic findings in the CNS tissue from ovarian mature teratomas were as follows: (i) CNS tissue tended to form a relatively thin, undulating, plate‐like structure that comprised the walls or septa of cystic tumors; (ii) most neurons were small or medium sized, and no CD34‐positive “ramifying cells” were observed; (iii) cytoplasmic processes of some astrocytes closely surrounded the walls of capillaries, suggesting formation of a blood–brain barrier; (iv) some ependymal cells exhibited a columnar shape and showed a pseudostratified arrangement, and these cells extended thick basal cytoplasmic processes into the neuropil; (v) a few choroid plexus epithelial cells showed melanin deposition, tubular transformation, or oncocytic changes; (vi) hamartoma‐like hyperplasia of arachnoid cells was noted beneath skin tissue; (vii) some CNS tissue showed formation of cerebral cortical structures exhibiting “gyration” with incompletely layered structures, and disruption of the glia limitans with spillage of cortical tissue into the “subarachnoid” space was also observed; and (viii) in the well‐formed cerebellar cortex, dendrites of Purkinje cells exhibited varied dysmorphic changes. These neuropathologic observations should lead to a deeper understanding of the pathogenesis of various lesions in the brain. [ABSTRACT FROM AUTHOR]

The cerebellum has historically been primarily associated with the regulation of precise motor functions. However, recent findings suggest that it also plays a pivotal role in the development of advanced cognitive functions, including learning, memory, and emotion regulation. Pathological changes in the cerebellum, whether congenital hereditary or acquired degenerative, can result in a diverse spectrum of disorders, ranging from genetic spinocerebellar ataxias to psychiatric conditions such as autism, and schizophrenia. While studies in animal models have significantly contributed to our understanding of the genetic networks governing cerebellar development, it is important to note that the human cerebellum follows a protracted developmental timeline compared to the neocortex. Consequently, employing animal models to uncover human-specific molecular events in cerebellar development presents significant challenges. The emergence of human induced pluripotent stem cells (hiPSCs) has provided an invaluable tool for creating human-based culture systems, enabling the modeling and analysis of cerebellar physiology and pathology. hiPSCs and their differentiated progenies can be derived from patients with specific disorders or carrying distinct genetic variants. Importantly, they preserve the unique genetic signatures of the individuals from whom they originate, allowing for the elucidation of human-specific molecular and cellular processes involved in cerebellar development and related disorders. This review focuses on the technical advancements in the utilization of hiPSCs for the generation of both 2D cerebellar neuronal cells and 3D cerebellar organoids. [ABSTRACT FROM AUTHOR]

Ataxia with anti-regulator of G-protein signaling 8 autoantibodies (RGS8-Abs) is an autoimmune disease recently described in four patients. The present study aimed to identify other patients with RGS8-Abs, describe their clinical features, including the link between RGS8-related autoimmune cerebellar ataxia (ACA) and cancer. Patients with RGS8-Abs were identified retrospectively in the biological collections of the French Reference Center for Paraneoplastic Neurological Syndrome and the University of California San Francisco Center for Encephalitis and Meningitis. Clinical data were collected, and cerebrospinal fluid, serum, and tumor pathological samples were retrieved to characterize the autoantibodies and the associated malignancies. Only three patients with RGS8-Abs were identified. All of them presented with a pure cerebellar ataxia of mild to severe course, unresponsive to current immunotherapy regimens for ACA. Two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, with very mild extension. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-related ACA. The present results and those of the four cases previously described suggest that RGS8-Abs define a new paraneoplastic neurological syndrome of extreme rarity found mostly in middle-aged males that associates pure cerebellar ataxia and a particular lymphoma specifically expressing the RGS8 antigen. As in other paraneoplastic ACA with intracellular antigen, the disease course is severe, and patients tend to exhibit a poor response to immune therapy. [ABSTRACT FROM AUTHOR]

Exposure to valproic acid (VPA), a common anti-seizure medication, in utero is a risk factor for autism spectrum disorder (ASD). People with ASD often display changes in the cerebellum, including volume changes, altered circuitry, and changes in Purkinje cell populations. ASD is also characterized by changes in the medial prefrontal cortex (mPFC), where excitatory/inhibitory balance is often altered. This study exposed rats to a high dose of VPA during gestation and assessed cognition and anxiety-like behaviors during young adulthood using a set-shifting task and the elevated plus maze. Inhibitory parvalbumin-expressing (PV +) neuron counts were assessed in the mPFC and cerebellar lobules VI and VII (Purkinje cell layers), which are known to modulate cognition. VPA males had increased PV + counts in crus I and II of lobule VII. VPA males also had decreased parvalbumin-expressing neuron counts in the mPFC. It was also found that VPA-exposed rats, regardless of sex, had increased parvalbumin-expressing Purkinje cell counts in lobule VI. In males, this was associated with impaired intra-dimensional shifting on a set-shifting task. Purkinje cell over proliferation may be contributing to the previously observed increase in volume of Lobule VI. These findings suggest that altered inhibitory signaling in cerebellar-frontal circuits may contribute to the cognitive deficits that occur within ASD. [ABSTRACT FROM AUTHOR]

[Display omitted] • We developed an aggressive multiple system atrophy-cerebellar variant mouse model. • In mice, human α-synuclein was expressed in oligodendrocytes via Tet-Off regulation. • We observed age-dependent phosphorylated α-synuclein deposition in glia and neurons. • Marked microglial and astrocytic reaction with inflammation in demyelinated lesions. • α-Synuclein oligomers spread from oligodendrocytes to astrocytes and neurons. Multiple system atrophy (MSA) is a severe α-synucleinopathy facilitated by glial reactions; the cerebellar variant (MSA-C) preferentially involves olivopontocerebellar fibres with conspicuous demyelination. A lack of aggressive models that preferentially involve olivopontocerebellar tracts in adulthood has hindered our understanding of the mechanisms of demyelination and neuroaxonal loss, and thus the development of effective treatments for MSA. We therefore aimed to develop a rapidly progressive mouse model that recaptures MSA-C pathology. We crossed Plp1 -tTA and tetO- SNCA*A53T mice to generate Plp1 -tTA::tetO- SNCA*A53T bi-transgenic mice, in which human A53T α-synuclein—a mutant protein with enhanced aggregability—was specifically produced in the oligodendrocytes of adult mice using Tet-Off regulation. These bi-transgenic mice expressed mutant α-synuclein from 8 weeks of age, when doxycycline was removed from the diet. All bi-transgenic mice presented rapidly progressive motor deterioration, with wide-based ataxic gait around 22 weeks of age and death around 30 weeks of age. They also had prominent demyelination in the brainstem/cerebellum. Double immunostaining demonstrated that myelin basic protein was markedly decreased in areas in which SM132, an axonal marker, was relatively preserved. Demyelinating lesions exhibited marked ionised calcium-binding adaptor molecule 1-, arginase-1-, and toll-like receptor 2-positive microglial reactivity and glial fibrillary acidic protein-positive astrocytic reactivity. Microarray analysis revealed a strong inflammatory response and cytokine/chemokine production in bi-transgenic mice. Neuronal nuclei-positive neuronal loss and patchy microtubule-associated protein 2-positive dendritic loss became prominent at 30 weeks of age. However, a perceived decrease in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta in bi-transgenic mice compared with wild-type mice was not significant, even at 30 weeks of age. Wild-type, Plp1 -tTA, and tetO- SNCA*A53T mice developed neither motor deficits nor demyelination. In bi-transgenic mice, double immunostaining revealed human α-synuclein accumulation in neurite outgrowth inhibitor A (Nogo-A)-positive oligodendrocytes beginning at 9 weeks of age; its expression was further increased at 10 to 12 weeks, and these increased levels were maintained at 12, 24, and 30 weeks. In an α-synuclein-proximity ligation assay, α-synuclein oligomers first appeared in brainstem oligodendrocytes as early as 9 weeks of age; they then spread to astrocytes, neuropil, and neurons at 12 and 16 weeks of age. α-Synuclein oligomers in the brainstem neuropil were most abundant at 16 weeks of age and decreased thereafter; however, those in Purkinje cells successively increased until 30 weeks of age. Double immunostaining revealed the presence of phosphorylated α-synuclein in Nogo-A-positive oligodendrocytes in the brainstem/cerebellum as early as 9 weeks of age. In quantitative assessments, phosphorylated α-synuclein gradually and successively accumulated at 12, 24, and 30 weeks in bi-transgenic mice. By contrast, no phosphorylated α-synuclein was detected in wild-type, tetO- SNCA*A53T , or Plp1 -tTA mice at any age examined. Pronounced demyelination and tubulin polymerisation, promoting protein-positive oligodendrocytic loss, was closely associated with phosphorylated α-synuclein aggregates at 24 and 30 weeks of age. Early inhibition of mutant α-synuclein expression by doxycycline diet at 23 weeks led to fully recovered demyelination; inhibition at 27 weeks led to persistent demyelination with glial reactions, despite resolving phosphorylated α-synuclein aggregates. In conclusion, our bi-transgenic mice exhibited progressively increasing demyelination and neuroaxonal loss in the brainstem/cerebellum, with rapidly progressive motor deterioration in adulthood. These mice showed marked microglial and astrocytic reactions with inflammation that was closely associated with phosphorylated α-synuclein aggregates. These features closely mimic human MSA-C pathology. Notably, our model is the first to suggest that α-synuclein oligomers may spread from oligodendrocytes to neurons in transgenic mice with human α-synuclein expression in oligodendrocytes. This model of MSA is therefore particularly useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA. [ABSTRACT FROM AUTHOR]

Abstract Background Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2. Methods Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis. Results Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death. Conclusion In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice.

Background: One of the organs in the human fetus that starts to differentiate extremely early and keeps doing so throughout the postnatal period is the cerebellum. The goal of this study was to create a nomogram using the chronological events that were occurring and the relationship with progressing gestational age. Granule cells and Purkinje cells play a crucial role in the normal development of the cerebellum. Any disruption at the cellular level can lead to abnormal migration of these cells, potentially resulting in hypoplasia of the cerebellar vermis. Methodology: Tissue specimens from 60 human fetuses were studied for histological changes after being grouped into four from 13th week to 32nd week. Fetuses with any neurological deficit were excluded from the study. Different layers were identified, and the thickness of each layer was noted. Results: The first two groups had three layers, but the composition was different in both. The marginal and mantle layers in the second group disappeared completely. The third group showed presence of five layers, with addition of lamina dissecans, appearing for a transient period. The fourth group had four layers. The thickness of external granular layer and internal granular layer (IGL) increased throughout, except that the IGL made an appearance from the second group only. Lamina dissecans appeared, causing a significant shift between 23 and 27 weeks. The fetus has a four-layered structure near term, with an external granular layer persisting throughout the early postnatal stage of life. Progression of pregnancy was positively connected with the molecular and Purkinje cell layer (PCL) thickness. Conclusion: Progression of pregnancy was positively connected with the molecular and PCL thickness. Age determination and neuropsychiatric disorders of the developing fetus may benefit from such a link.

Key points Neurons of the inferior olive (IO) fire action potentials with large, long‐lasting afterdepolarizations (ADPs). Broader ADPs support more spikes in climbing fibre axons and evoke longer bursts of complex spikes in Purkinje cells, which affect the magnitude and sign of cerebellar synaptic plasticity. In the present study, we investigated the ionic mechanisms that regulate IO action potential waveforms by making whole‐cell recordings in brainstem slices from C57BL6/J mice. IO spikes evoked from rest had ADPs of ∼30 ms. After 500‐ms hyperpolarizations, however, evoked action potentials were brief (1–2 ms), lacking ADPs altogether. Because such preconditioning should maximally recruit depolarizing Ih and T‐type currents and minimize repolarizing Ca‐dependent currents known to shape the ADP, the rapid action potential downstroke suggested additional, dominant recovery of voltage‐gated K currents at negative voltages. Under voltage clamp, outward currents evoked from –98 mV included large, voltage‐gated, rapidly inactivating ‘A‐type’ K currents. These currents had a steep availability curve with half‐inactivation at –85 mV, suitable for recruitment by small hyperpolarizations. The fast decay time constant increased with depolarization, as is typical of KV4 channels. The KV4 channel blocker AmmTx3 almost eliminated inactivating currents and broadened action potentials evoked from strongly negative potentials by ∼8‐fold. Optogenetic stimulation of inhibitory cerebellar nucleo‐olivary terminals hyperpolarized IO cells sufficiently to abolish the ADP. The data support the idea that currents through KV4 channels control action potential waveforms in IO cells, shortening ADPs during synaptic inhibition or troughs of membrane potential oscillations, thereby controlling the number of climbing fibre action potentials that propagate to the cerebellum. Neurons in the mouse inferior olive (IO) express a large, inactivating, voltage‐gated A‐type K current carried by KV4 channels. IO action potentials evoked from rest have large, long afterdepolarizations that disappear with pre‐spike hyperpolarizations of 5–15 mV. The steep voltage‐sensitivity and rapid recovery of KV4 channels regulates the duration of the afterdepolarization over more than one order of magnitude. Factors such as synaptic inhibition are sufficient to recruit KV4 channels and eliminate afterdepolarization (ADP). By controlling the ADP, KV4 channels can set the number of climbing fibre action potentials relayed to the cerebellum and regulate plasticity implicated in motor learning. [ABSTRACT FROM AUTHOR]

Senescence of nondividing neurons remains an immature concept, with especially the regulatory molecular mechanisms of senescence-like phenotypes and the role of proteins associated with neurodegenerative diseases in triggering neuronal senescence remaining poorly explored. In this study, we reveal that the nucleolar polyglutamine binding protein 3 (PQBP3; also termed NOL7), which has been linked to polyQ neurodegenerative diseases, regulates senescence as a gatekeeper of cytoplasmic DNA leakage. PQBP3 directly binds PSME3 (proteasome activator complex subunit 3), a subunit of the 11S proteasome regulator complex, decreasing PSME3 interaction with Lamin B1 and thereby preventing Lamin B1 degradation and senescence. Depletion of endogenous PQBP3 causes nuclear membrane instability and release of genomic DNA from the nucleus to the cytosol. Among multiple tested polyQ proteins, ataxin-1 (ATXN1) partially sequesters PQBP3 to inclusion bodies, reducing nucleolar PQBP3 levels. Consistently, knock-in mice expressing mutant Atxn1 exhibit decreased nuclear PQBP3 and a senescence phenotype in Purkinje cells of the cerebellum. Collectively, these results suggest homologous roles of the nucleolar protein PQBP3 in cellular senescence and neurodegeneration. Synopsis: Senescence of nondividing cells such as neurons is thought to promote neurodegenerative diseases, however, its molecular control remains unclear. Here, the nucleolar protein PQBP3 (also termed NOL7), associated with polyQ diseases, is shown to prevent cellular senescence by antagonising genomic DNA leakage to the cytosol. PQBP3 is an intrinsically disordered protein localized primarily at the periphery of the nucleolus. PQBP3 depletion increases nuclear membrane instability and cytoplasmic DNA leakage in human cells, inducing senescence. PQBP3 interacts with the proteasome activator subunit PSME3, stabilizing Lamin B1 and the nuclear membrane. Decreased nuclear PQBP3, the polyQ protein ATXN1, and cellular senescence are associated with polyQ disease pathology in cerebellar Purkinje cells in mice. The nucleolar polyQ-binding protein PQBP3/NOL7 protects neurons from cellular senescence by stabilizing the nuclear membrane and preventing genomic DNA leakage. [ABSTRACT FROM AUTHOR]

The cerebellum plays an important role in diverse brain functions, ranging from motor learning to cognition. Recent studies have suggested that molecular and cellular heterogeneity within cerebellar lobules contributes to functional differences across the cerebellum. However, the specific relationship between molecular and cellular heterogeneity and diverse functional outputs of different regions of the cerebellum remains unclear. Here, we describe a previously unappreciated form of synaptic heterogeneity at parallel fiber synapses to Purkinje cells in the mouse cerebellum (both sexes). In contrast to uniform fast synaptic transmission, we found that the properties of slow synaptic transmission varied by up to threefold across different lobules of the mouse cerebellum, resulting in surprising heterogeneity. Depending on the location of a Purkinje cell, the time of peak of slow synaptic currents varied by hundreds of milliseconds. The duration and decay time of these currents also spanned hundreds of milliseconds, based on lobule. We found that, as a consequence of the heterogeneous synaptic dynamics, the same brief input stimulus was transformed into prolonged firing patterns over a range of timescales that depended on Purkinje cell location. [ABSTRACT FROM AUTHOR]

In current study, we used Nissl staining to examine the histological structure of the juvenile Chinese alligator brain, and immunohistochemistry (IHC) staining to detail the serotonin (5-hydroxytryptamine, 5-HT) localization and morphology of neurons belonging to the serotonergic system. Nissl staining revealed that the Chinese alligator brain was divided into four regions (telencephalon, diencephalon, brainstem, and cerebellum) and a connected ventricular system (containing the pair of lateral ventricles, third ventricle, fourth ventricle and the aqueduct). According to the IHC results, 5-HT immunoreactive (5-HT-IR) neurons were primarily observed in the cerebral cortex, the hypothalamic paraventricular nucleus (PH), tectum and tegmentum of the optic lobes, the medial longitudinal fasciculus (Flm) of medulla oblongata and the cerebellar cortex. 5-HT-IR fibers were mostly located lateral to the hypothalamic paraventricular nucleus (PH), in the medial vestibular nucleus (MVe) of the medulla oblongata, and in the choroid plexus (CP) of the lateral ventricles. Additionally, our findings paralleled those results of other reptiles; nevertheless, some distinctions in terms of both histological architecture and function were identified. The layering of the cerebral cortex and tectum, as well as the arrangement of Purkinje cells, differed between reptile brains. The distribution of 5-HT-IR neurons varied in the layer of cerebral and cerebellar cortex when compared to other reptiles. Within the diencephalon, 5-HT-IR neurons formed distinct nuclei in the hypothalamic paraventricular nucleus (PH), but few in the infundibular recess. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone." The correction states that there was an error in Figure 6D, Figure 9D, and Figure 10A of the original publication, which occurred during the labeling of the photos and plate preparation. The corrected figures have been included in the notice, and the authors assure that the scientific conclusions remain unaffected. The updated publication has been approved by the Academic Editor. [Extracted from the article]

Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell type-specific role in cerebellar Purkinje cells that is essential for normal motor function. In the absence of RIM4, Purkinje cell intrinsic firing is reduced and caffeine-sensitive, and dendritic integration of climbing fibre input is disturbed. Mice lacking RIM4, but not mice lacking RIM1/2, selectively in Purkinje cells exhibit a severe, hours-long paroxysmal dystonia. These episodes can also be induced by caffeine, ethanol or stress and closely resemble the deficits seen with mutations of the PNKD (paroxysmal non-kinesigenic dystonia) gene. Our data reveal essential postsynaptic functions of RIM proteins and show non-overlapping specialized functions of a small isoform despite high homology to a single domain in the full-length proteins. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult‐onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive. Objective: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation. Methods: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing. Results: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG‐PET demonstrated brain hypometabolism and [11C]Flumazenil‐PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls. Conclusions: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations. [ABSTRACT FROM AUTHOR]

Lhermitte-Duclos Disease (LDD) is a rare condition characterized by a cerebellar mass composed of dysplastic ganglion cells. It is classified as a glioneuronal and neuronal tumor. The exact nature of LDD is still unclear, with debate over whether it is hamartomatous or neoplastic in nature. LDD is associated with Cowden syndrome (CS), a rare genetic disorder that increases the risk of certain cancers. The activation of the PTEN/AKT/mTOR pathway is believed to play a role in the pathogenesis of LDD. Diagnosis of LDD may prompt further screening for CS and associated malignancies. Surgical resection is the main treatment for LDD, and long-term follow-up is important for early detection of associated malignancies. [Extracted from the article]

Tebuconazole (TEB) is a common triazole sterol demethylation inhibitor fungicide utilized to manage a variety of diseases in crops like cereals, fruits, and vegetables. The aim of this work was to assess the effects of TEB on the structure of the cerebellum in adult albino rats and possible protective impact of co-administration of Gallic acid (GA). Four groups of forty adult male albino rats were randomly selected, and the rats in group I received corn oil through daily gavage for 4 weeks. Group II received GA dissolved in the normal saline at a dose of 100 mg/kg through daily gavage for 4 weeks, group III administered with TEB dissolved in corn oil at its acceptable daily intake dose (0.02 mg/kg body weight) through daily gavage for 4 weeks, group IV rats received both TEB and GA. For light microscopic, ultrastructural, and immunohistochemical investigations, cerebellar specimens were prepared. TEB exposure led to neuronal damage in the form of degenerated Purkinje cells with vacuolated cytoplasm, areas of lost Purkinje cells, the basket cells appeared vacuolated with degenerated neuropil, the granule cells clumped with congested areas between them, dilated cerebellar islands, weak positive bcl2 immunoreactions in the Purkinje cells, and numerous GFAP-positive astrocytes. GA mitigated TEB-mediated histological changes in the cerebellar cortex. We concluded that TEB caused Purkinje neurons in the rat cerebellar cortex to degenerate and undergo apoptosis. GA had a neuroprotective benefit against TEB toxicity in the rat cerebellar cortex. [ABSTRACT FROM AUTHOR]

The synapses between parallel fibers and Purkinje cells play a pivotal role in cerebellar function. They are intricately governed by a variety of presynaptic receptors, notably by type 4metabotropic glutamate (mGlu4) receptors and type 1 adenosine (A1) receptors both of which curtail glutamate release upon activation. Despite their pivotal role in regulating synaptic transmission within the cerebellar cortex, functional interactions between mGlu4 and A1 receptors have remained relatively unexplored. To bridge this gap, our study delves into how mGlu4 receptor activity influences A1 receptor-mediated alterations in excitatory transmission. Employing a combination of whole-cell patch clamp recordings of Purkinje cells and parallel fiber presynaptic fluorometric calcium measurements in acute rat andmouse cerebellar cortical slices, our results reveal functional interactions between these receptor types. These findings hold implications for understanding potential roles of these presynaptic receptors in neuroprotection during pathophysiological conditions characterized by elevated glutamate and adenosine levels. [ABSTRACT FROM AUTHOR]

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre-and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties. [ABSTRACT FROM AUTHOR]

Synaptic connectivity defines groups of neurons that engage in correlated activity during specific functional tasks. These co-active groups of neurons form ensembles, the operational units involved in, for example, sensory perception, motor coordination and memory (then called an engram). Traditionally, ensemble formation has been thought to occur via strengthening of synaptic connections via long-term potentiation (LTP) as a plasticity mechanism. This synaptic theory of memory arises from the learning rules formulated by Hebb and is consistent with many experimental observations. Here, we propose, as an alternative, that the intrinsic excitability of neurons and its plasticity constitute a second, non-synaptic mechanism that could be important for the initial formation of ensembles. Indeed, enhanced neural excitability is widely observed in multiple brain areas subsequent to behavioral learning. In cortical structures and the amygdala, excitability changes are often reported as transient, even though they can last tens of minutes to a few days. Perhaps it is for this reason that they have been traditionally considered as modulatory, merely supporting ensemble formation by facilitating LTP induction, without further involvement in memory function (memory allocation hypothesis). We here suggest-based on two lines of evidence--that beyond modulating LTP allocation, enhanced excitability plays a more fundamental role in learning. First, enhanced excitability constitutes a signature of active ensembles and, due to it, subthreshold synaptic connections become suprathreshold in the absence of synaptic plasticity (iceberg model). Second, enhanced excitability promotes the propagation of dendritic potentials toward the soma and allows for enhanced coupling of EPSP amplitude (LTP) to the spike output (and thus ensemble participation). This permissive gate model describes a need for permanently increased excitability, which seems at odds with its traditional consideration as a short-lived mechanism. We propose that longer modifications in excitability are made possible by a low threshold for intrinsic plasticity induction, suggesting that excitability might be on/offmodulated at short intervals. Consistent with this, in cerebellar Purkinje cells, excitability lasts days to weeks, which shows that in some circuits the duration of the phenomenon is not a limiting factor in the first place. In our model, synaptic plasticity defines the information content received by neurons through the connectivity network that they are embedded in. However, the plasticity of cell-autonomous excitability could dynamically regulate the ensemble participation of individual neurons as well as the overall activity state of an ensemble. [ABSTRACT FROM AUTHOR]

The cerebellum has a long, protracted developmental period that spans from the embryonic to postnatal periods; as a result, it is more sensitive to intrauterine and postnatal insults like nutritional deficiencies. Folate is crucial for foetal and early postnatal brain development; however, its effects on cerebellar growth and development are unknown. The aim of this study was to examine the effects of maternal folate intake on the histomorphology and cell density of the developing cerebellum. Twelve adult female rats (rattus norvegicus) were randomly assigned to one of four premixed diet groups: standard (2 mg/kg), folate‐deficient (0 mg/kg), folate‐supplemented (8 mg/kg) or folate supra‐supplemented (40 mg/kg). The rats started their diets 14 days before mating and consumed them throughout pregnancy and lactation. On postnatal days 1, 7, 21 and 35, five pups from each group were sacrificed, and their brains were processed for light microscopic analysis. Histomorphology and cell density of the external granule, molecular, Purkinje and internal granule layers were obtained. The folate‐deficient diet group had smaller, dysmorphic cells and significantly lower densities of external granule, molecular, Purkinje and internal granule cells. Although the folate‐enriched groups had greater cell densities than the controls, the folate‐supplemented group had considerably higher cell densities than the supra‐supplemented group. The folate supra‐supplemented group had ectopic Purkinje cells in the internal granule cell layer. These findings imply that a folate‐deficient diet impairs cellular growth and reduces cell density in the cerebellar cortex. On the other hand, folate supplementation increases cell densities, but there appears to be an optimal dose of supplementation since excessive folate levels may be detrimental. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease type C1 (NPC1, MIM 257220) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of Npc1-/- displays a rapidly progressing form of Npc1 disease, which is characterized by weight loss, ataxia, and increased cholesterol storage. Npc1-/- mice receiving a combined therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HPßCD) showed prevention of Purkinje cell loss, improved motor function and reduced intracellular lipid storage. Although therapy of Npc1-/- mice with COMBI, MIGLU or HPßCD resulted in the prevention of body weight loss, reduced total brain weight was not positively influenced. Methods: In order to evaluate alterations of different brain areas caused by pharmacotherapy, fresh volumes (volumes calculated from the volumes determined from paraffin embedded brain slices) of various brain structures in sham- and drug-treated wild type and mutant mice were measured using stereological methods. Results: In the wild type mice, the volumes of investigated brain areas were not significantly altered by either therapy. Compared with the respective wild types, fresh volumes of specific brain areas, which were significantly reduced in sham-treated Npc1-/- mice, partly increased after the pharmacotherapies in all treatment strategies; most pronounced differences were found in the CA1 area of the hippocampus and in olfactory structures. Discussion: Volumes of brain areas of Npc1-/- mice were not specifically changed in terms of functionality after administering COMBI, MIGLU, or HPßCD. Measurements of fresh volumes of brain areas in Npc1-/- mice could monitor region-specific changes and response to drug treatment that correlated, in part, with behavioral improvements in this mouse model. [ABSTRACT FROM AUTHOR]

Introduction: Preterm newborns struggle with maintaining an adequate respiratory pattern; early caffeine administration is suggested to stimulate respiration and reduce bronchopulmonary dysplasia, however, its consequences on the immature cerebellum remains unknown. This study aimed to assess the impact of early caffeine administration, at standard and high doses, accompanied by supplemental oxygen on cerebellar development in an experimental model. Methods: Five groups of Wistar pups were formed (n = 8 offspring/group): (a) negative control: no intervention; (b) placebo: pups remaining from birth until the 7th day of life (DOL) exposed to fractional inspired oxygen (FiO2) 45%, resembling preterm infant condition and as a placebo, 0.2 mL oral 5% dextrose, from the first DOL until the 14th DOL; (c) caffeine group: oral caffeine, 1st DOL 20 mg/kg, and from 2nd to 14th DOL, 5 mg/kg (standard dose); (d) caffeine at the standard dose, plus O2: during the first 7 DOLs (FiO2: 45%); (e) caffeine: 40 mg/kg in the first DOL, 10 mg/kg the next 14 DOLs, plus O2 in the first 7 DOLs (FiO2: 45%). Subjects were sacrificed on their 15th DOL; measurements were taken from the cerebellum, specifically the external granular layer (EGL) and molecular layer (ML), with quantification of cell migration. Results: Caffeine administration in pups resulted in a delay in cerebellum development based on persistent transitional EGL cells; this finding was exacerbated in groups exposed to caffeine plus O2, as evident from the thicker EGL. The negative control group showed near-complete cell migration with a thicker ML and a significantly smaller EGL. Conclusions: Early caffeine administration in newborn rats disrupts cerebellar cortex cell processes and connectivity pathways, with exacerbated effects in groups receiving caffeine plus O2. [ABSTRACT FROM AUTHOR]

The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70's, a comprehensive review of contemporary models is currently lacking. Here, we provide an overviewof PCmodels, ranging fromthe ones focused on single cell intracellular PC dynamics, through complexmodels which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computationalmodels that capture real-life PC dynamics in the context of cerebellar computations. [ABSTRACT FROM AUTHOR]

Introduction: Reelin is a neuropeptide responsible for the migration and positioning of pyramidal neurons, interneurons, and Purkinje cells. In adulthood, it still supports neuroplasticity, especially dendritic spines formation and glutamatergic neurotransmission. Genetic studies have confirmed the involvement of reelin system failure in the etiopathogenesis of mental diseases, including schizophrenia. Given the role of reelin in brain cytoarchitectonics and the regularly observed reduction in its activity in prefrontal areas in cases of schizophrenia, dysfunction of the reelin pathway fits the neurodevelopmental hypothesis of schizophrenia, both as a biochemical predisposition and/or the ultimate trigger of psychosis and as a biosocial factor determining the clinical course, and finally, as a potential target for disease monitoring and treatment. Aim: The purpose of this study was to examine associations of the reelin blood level with clinical and neurocognitive parameters during an intensive, structured neurofeedback therapy of patients with schizophrenia. Methods: Thirty-seven male patients with paranoid schizophrenia were randomly divided into two groups: a group with 3-month neurofeedback as an add-on to ongoing antipsychotic treatment (NF, N18), and a control group with standard social support and antipsychotic treatment (CON, N19). The reelin serum concentration, clinical and neurocognitive tests were compared between the groups. Results: After 3-month trial (T2), the reelin serum level increased in the NF group vs. the CON group. The negative and general symptoms of PANSS (Positive and Negative Syndrome Scale) were reduced significantly more in the NF group at T2, and the d2 (d2 Sustained Attention Test) and BCIS (Beck Cognitive Insight Scale) scores improved only in the NF group. The AIS scores improved more dynamically in the NF group, but not enough to differentiate them from the CON group at T2. Conclusions: The clinical and neurocognitive improvement within the 3-month NF add-on therapy trial was associated with a significant increase of reelin serum level in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Background: Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. Methods: Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. Results: A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 μm; HGINV 37 ± 5 μm; WB 28 ± 3 μm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. Conclusion: The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism. Author summary: Giardia intestinalis (Syn. G. duodenalis or G. lamblia), is a protozoan flagellate that parasitizes humans and animals and is transmitted by the ingestion of food or water contaminated with cysts or via person-to-person contact. Causes diarrhoea. Affects children and adults worldwide. Giardiasis is known to have long-term effects. When giardiasis occurs in the first two years of a child's life, it is associated with stunted growth and psychomotor and cognitive retardation. Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. We modelled Giardia infection in gerbils in the first days of postnatal life and found morphological changes that suggest neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life. For the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor-cognitive delay associated with giardiasis. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism. [ABSTRACT FROM AUTHOR]