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Synaptic-vesicle (SV) recruitment is thought to maintain reliable neurotransmitter release during high-frequency signaling. However, the mechanism underlying the SV reloading for sustained neurotransmission at central synapses remains unknown. To elucidate this, we performed direct observations of SV reloading and mobility at a single-vesicle level near the plasma membrane in cerebellar mossy fiber terminals using total internal reflection fluorescence microscopy, together with simultaneous recordings of membrane fusion by capacitance measurements. We found that actin disruption abolished the rapid SV recruitment and reduced sustained release. In contrast, induction of actin polymerization and stabilization did not affect vesicle recruitment and release, suggesting that the presence of actin filaments, rather than actin dynamics, was required for the rapid recruitment. Single-particle tracking experiments of quantum dot-labeled vesicles, which allows nanoscale resolution of vesicle mobility, revealed that actin disruption caused vesicles to diffuse more rapidly. Hidden Markov modeling with Bayesian inference revealed that SVs had two diffusion states under normal conditions: free-diffusing and trapped. After disruption of the actin filament, vesicles tended to have only the free-diffusing state. F-actin staining showed that actin filaments were localized outside the active zones (AZs) and surrounded some SV trajectories. Perturbation of SV mobility, possibly through interference with biomolecular condensates, also suggested that the restricted diffusion state determined the rate of SV recruitment. We propose that actin filaments confined SVs near the AZ to achieve rapid and efficient recruitment followed by priming and sustained synaptic transmission. [ABSTRACT FROM AUTHOR]

Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen‐activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual‐specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by stimulating neural progenitor cell (NPC) differentiation in AD mice remains unclear. Our study demonstrates an association between DUSP16 SNPs and clinical progression in individuals with mild cognitive impairment (MCI). Besides, increased DUSP16 expression was detected in both 3xTg and SAMP8 mouse models of AD, accompanied by NPC neural differentiation impairments. By silencing DUSP16, the induction of neural differentiation, synaptic transmission, and cognitive benefits were observed in both AD mice. Furthermore, DUSP16 was involved in the process of NPC differentiation through regulating c‐Jun N‐terminal kinase (JNK) phosphorylation and SOX2 expression. Moreover, ETS transcription factor (ELK1) was involved in the DUSP16 transcription, which resulted in the upregulation of DUSP16 at the state of AD. Our data uncovers a potential regulatory role for DUSP16 in adult hippocampal neurogenesis (AHN) and provides a possibility to find a novel strategy for AD intervention. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption. [ABSTRACT FROM AUTHOR]

Key points Basket cells are inhibitory interneurons in cortical structures with the potential to efficiently control the activity of their postsynaptic partners. Although their contribution to higher order cognitive functions associated with the medial prefrontal cortex (mPFC) relies on the characteristics of their synaptic connections, the way that they are embedded into local circuits is still not fully uncovered. Here, we determined the synaptic properties of excitatory and inhibitory connections between pyramidal neurons (PNs), cholecystokinin‐containing basket cells (CCKBCs) and parvalbumin‐containing basket cells (PVBCs) in the mouse mPFC. By performing paired recordings, we revealed that PVBCs receive larger unitary excitatory postsynaptic currents from PNs with shorter latency and faster kinetic properties compared to events evoked in CCKBCs. Also, unitary inhibitory postsynaptic currents in PNs were more reliably evoked by PVBCs than by CCKBCs, yet the former connections showed profound short‐term depression. Moreover, we demonstrated that CCKBCs and PVBCs in the mPFC are connected with each other. Because alterations in PVBC function have been linked to neurological and psychiatric conditions such as Alzheimer's disease and schizophrenia and CCKBC vulnerability might play a role in mood disorders, a deeper understanding of the general features of basket cell synapses could serve as a reference point for future investigations with therapeutic objectives. Cholecystokinin‐ (CCKBCs) and parvalbumin‐expressing basket cells (PVBCs) have distinct passive and active membrane properties. Pyramidal neurons give rise to larger unitary excitatory postsynaptic currents in PVBCs compared to events in CCKBCs. Unitary inhibitory postsynaptic currents in pyramidal neurons are more reliably evoked by PVBCs than by CCKBCs. Basket cells form chemical synapses and gap junctions with their own cell type. The two basket cell types are connected with each other. [ABSTRACT FROM AUTHOR]

Ionic driving forces provide the net electromotive force for ion movement across receptors, channels, and transporters, and are a fundamental property of all cells. In the nervous system, fast synaptic inhibition is mediated by chloride permeable GABAA and glycine receptors, and single-cell intracellular recordings have been the only method for estimating driving forces across these receptors (DFGABAA). Here we present a tool for quantifying inhibitory receptor driving force named ORCHID: all-Optical Reporting of CHloride Ion Driving force. We demonstrate ORCHID's ability to provide accurate, high-throughput measurements of resting and dynamic DFGABAA from genetically targeted cell types over multiple timescales. ORCHID confirms theoretical predictions about the biophysical mechanisms that establish DFGABAA, reveals differences in DFGABAA between neurons and astrocytes, and affords the first in vivo measurements of intact DFGABAA. This work extends our understanding of inhibitory synaptic transmission and demonstrates the potential for all-optical methods to assess ionic driving forces. Single-cell intracellular recordings have been used as the primary tool for estimating driving forces across inhibitory receptors within the nervous system. Here, the authors present ORCHID as an all-optical method to measure inhibitory receptor driving forces in targeted brain cell types. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a leading component of several neurodegenerative and neurodevelopmental diseases, profoundly impacting on the individual, the family, and society at large. Cognitive pathologies are driven by a multiplicity of factors, from genetic mutations and genetic risk factors, neurotransmitter-associated dysfunction, abnormal connectomics at the level of local neuronal circuits and broader brain networks, to environmental influences able to modulate some of the endogenous factors. Otherwise healthy older adults can be expected to experience some degree of mild cognitive impairment, some of which fall into the category of subjective cognitive deficits in clinical practice, while many neurodevelopmental and neurodegenerative diseases course with more profound alterations of cognition, particularly within the spectrum of the dementias. Our knowledge of the underlying neuropathological mechanisms at the root of this ample palette of clinical entities is far from complete. This review looks at current knowledge on synaptic modifications in the context of cognitive function along healthy ageing and cognitive dysfunction in disease, providing insight into differential diagnostic elements in the wide range of synapse alterations, from those associated with the mild cognitive changes of physiological senescence to the more profound abnormalities occurring at advanced clinical stages of dementia. I propose the term "cognitive synaptopathy" to encompass the wide spectrum of synaptic pathologies associated with higher brain function disorders. [ABSTRACT FROM AUTHOR]

A whole‐cell patch‐clamp study was carried out to investigate membrane and synaptic properties of cholinergic interneurons in the striatum of aristaless‐related homeobox gene (ARX) mutant mice. Brain slices were prepared from mice knocked in two types of ARX, P355L (PL) and 333ins (GCG)7 (GCG). The input resistance of cholinergic interneurons in PL or GCG mice was significantly smaller than that in wild type (WT), whereas resting membrane potential, threshold of action potentials, spontaneous firing rate, sag ratio or afterhyperpolarization of the mutant mice were not significantly different from those of WT mice. In GCG mice, NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) evoked in cholinergic interneurons was significantly smaller than that in WT and PL mice, whereas the ratio between PL and WT mice was not significantly different. Although inhibitory effects induced by dopamine D2‐like receptor activation on the inhibitory postsynaptic currents (IPSCs) were not significantly different between WT and PL or GCG mice, increase in the paired pulse ratio of IPSCs by dopamine D2‐like receptor activation was abolished in PL and GCG mice. The present results have found abnormalities of neuronal activities as well as its modulation in the basal ganglia in ARX mutant mice, clarifying basic mechanisms underlying related disorders. [ABSTRACT FROM AUTHOR]

Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines. Synopsis: Neurotransmitters are key for synaptic transmission at axon terminals, but their transport modalities remain debated. This study demonstrates that coupling of histamine synthesis with its loading into synaptic vesicles by anchoring histidine decarboxylase (HDC) to synaptic vesicles is critical to maintaining neurotransmission and preventing cytotoxic side effects. Coupling histamine synthesis with synaptic vesicle loading is critical for neurotransmitter homeostasis and synaptic transmission. HDC is co-transported with synaptic vesicles to axonal terminals through binding with vesicle-fusing ATPase NSF1. HDC remaining in soma is degraded by the E3 ubiquitin ligase POE via the proteasome. Aberrant accumulation of histamine in the soma is cytotoxic and causes retinal degeneration. Anchoring of histidine decarboxylase to synaptic vesicles is critical to maintaining neurotransmission and preventing cytotoxic side effects. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) has been associated with deficits in working memory as well as underlying gamma oscillation power. Consistent with this, overall reductions in cortical excitation have also been described with MDD. In previous work, we have demonstrated that the monoamine reuptake inhibitor venlafaxine increases gamma oscillation power in ex vivo hippocampal slices and that this is associated with concomitant increases in pyramidal arbour and reduced levels of plasticity‐restricting perineuronal nets (PNNs). In the present study, we have examined the effects of chronic treatment with pramipexole (PPX), a D3 dopamine receptor agonist, for its effects on gamma oscillation power as measured by in vivo electroencephalography (EEG) recordings in female BALB/c and C57Bl6 mice. We observe a modest but significant increase in 20–50 Hz gamma power with PPX in both strains. Additionally, biochemical analysis of prefrontal cortex lysates from PPX‐treated BALB/c mice shows a number of changes that could contribute to, or follow from, increased pyramidal excitability and/or gamma power. PPX‐associated changes include reduced levels of specific PNN components as well as tissue inhibitor of matrix metalloproteases‐1 (TIMP‐1), which inhibits long‐term potentiation of synaptic transmission. Consistent with its effects on gamma power, PNN proteins and TIMP‐1, chronic PPX treatment also improves working memory and reduces anhedonia. Together these results add to an emerging literature linking extracellular matrix and/or gamma oscillation power to both mood and cognition. [ABSTRACT FROM AUTHOR]

Acute liver dysfunction commonly leads to rapid increases in ammonia concentrations in both the serum and the cerebrospinal fluid. These elevations primarily affect brain astrocytes, causing modifications in their structure and function. However, its impact on neurons is not yet fully understood. In this study, we investigated the impact of elevated ammonium chloride levels (NH4Cl, 5 mM) on synaptic transmission onto CA1 pyramidal neurons in mouse organotypic entorhino-hippocampal tissue cultures. We found that acute exposure to NH4Cl reversibly reduced excitatory synaptic transmission and affected CA3-CA1 synapses. Notably, NH4Cl modified astrocytic, but not CA1 pyramidal neuron, passive intrinsic properties. To further explore the role of astrocytes in NH4Clinduced attenuation of synaptic transmission, we used methionine sulfoximine to target glutamine synthetase, a key astrocytic enzyme for ammonia clearance in the central nervous system. Inhibition of glutamine synthetase effectively prevented the downregulation of excitatory synaptic activity, underscoring the significant role of astrocytes in adjusting excitatory synapses during acute ammonia elevation. [ABSTRACT FROM AUTHOR]

α-Neurexins are essential and highly expressed presynaptic cell-adhesion molecules that are frequently linked to neuropsychiatric and neurodevelopmental disorders. Despite their importance, how the elaborate extracellular sequences of α-neurexins contribute to synapse function is poorly understood. We recently characterized the presynaptic gain-of-function phenotype caused by a missense mutation in an evolutionarily conserved extracellular sequence of neurexin-3α (A687T) that we identified in a patient diagnosed with profound intellectual disability and epilepsy. The striking A687T gain-of-function mutation on neurexin-3α prompted us to systematically test using mutants whether the presynaptic gain-of-function phenotype is a consequence of the addition of side-chain bulk (i.e., A687V) or polar/hydrophilic properties (i.e., A687S). We used multidisciplinary approaches in mixed-sex primary hippocampal cultures to assess the impact of the neurexin-3αA687 residue on synapse morphology, function and ligand binding. Unexpectedly, neither A687V nor A687S recapitulated the neurexin-3α A687T phenotype. Instead, distinct from A687T, molecular replacement with A687S significantly enhanced postsynaptic properties exclusively at excitatory synapses and selectively increased binding to neuroligin-1 and neuroligin-3 without changing binding to neuroligin-2 or LRRTM2. Importantly, we provide the first experimental evidence supporting the notion that the position A687 of neurexin-3α and the N-terminal sequences of neuroligins may contribute to the stability of α-neurexin--neuroligin-1 trans-synaptic interactions and that these interactions may specifically regulate the postsynaptic strength of excitatory synapses. [ABSTRACT FROM AUTHOR]

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (AMPARs) mediate rapid excitatory synaptic transmission in the mammalian brain, primarily driven by the neurotransmitter glutamate. The modulation of AMPAR activity, particularly calcium‐permeable AMPARs (CP‐AMPARs), is crucially influenced by various auxiliary subunits. These subunits are integral membrane proteins that bind to the receptor's core and modify its functional properties, including ion channel kinetics and receptor trafficking. This review comprehensively catalogs all known AMPAR auxiliary proteins, providing vital insights into the biochemical mechanisms governing synaptic modulation and the specific impact of CP‐AMPARs compared to their calcium‐impermeable AMPA receptor (CI‐AMPARs). Understanding the complex interplay between AMPARs and their auxiliary subunits in different brain regions is essential for elucidating their roles in cognitive functions such as learning and memory. Importantly, alterations in these auxiliary proteins' expression, function or interactions have been implicated in various neurological disorders. Aberrant signaling through CP‐AMPARs, in particular, is associated with severe synaptic dysfunctions across neurodevelopmental, neurodegenerative and psychiatric conditions. Targeting the distinct properties of AMPAR‐auxiliary subunit complexes, especially those involving CP‐AMPARs, could disclose new therapeutic strategies, potentially allowing for more precise interventions in treating complex neuronal disorders. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested by various neurological impairments. The endocannabinoid system (ECS) is a lipid signalling network, which plays multiple roles in the central nervous system and the periphery, including synaptic signal transmission and modulation of inflammation. The ECS has been identified as a potential target for the development of novel therapeutic interventions in MS patients. It remains unclear whether ECS-associated metabolites are changed in MS and could serve as biomarkers in blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics to matching CSF and serum samples of 74 MS and 80 non-neuroinflammatory control patients. We found that MS-associated lipidomic changes overall did not coincide between CSF and serum. While glucocorticoids correlated positively, only the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) showed a weak positive correlation (r = 0.3, p < 0.05) between CSF and serum. Peptide endocannabinoids could be quantified for the first time in CSF but did not differ between MS and controls. MS patients showed elevated levels of prostaglandin E2 and steaorylethanolamide in serum, and 2-oleoylglycerol and cortisol in CSF. Sex-specific differences were found in CSF of MS patients showing increased levels of 2-AG and glucocorticoids in males only. Overall, arachidonic acid was elevated in CSF of males. Interestingly, CSF eCBs correlated positively with age only in the control patients due to the increased levels of eCBs in young relapsing-remitting MS patients. Our findings reveal significant discrepancies between CSF and serum, underscoring that measuring eCBs in blood matrices is not optimal for detecting MS-associated changes in the central nervous system. The identified sex and age-specific changes of analytes of the stress axis and ECS specifically in the CSF of MS patients supports the role of the ECS in MS and may be relevant for drug development strategies. [ABSTRACT FROM AUTHOR]

Key points Intersectin‐1 (Itsn1) is a scaffold protein that plays a key role in coupling exocytosis and endocytosis of synaptic vesicles (SVs). However, it is unclear whether and how Itsn1 regulates these processes to support efficient neurotransmission during development. To address this, we examined the calyx of Held synapse in the auditory brainstem of wild‐type and Itsn1 mutant mice before (immature) and after (mature) the onset of hearing. Itsn1 was present in the pre‐ and postsynaptic compartments at both developmental stages. Loss of function of Itsn1 did not alter presynaptic action potentials, Ca2+ entry via voltage‐gated Ca2+ channels (VGCCs), transmitter release or short‐term depression (STD) induced by depletion of SVs in the readily releasable pool (RRP) in either age group. Yet, fast Ca2+‐dependent recovery from STD was attenuated in mature mutant synapses, while it was unchanged in immature mutant synapses. This deficit at mature synapses was rescued by introducing the DH–PH domains of Itsn1 into the presynaptic terminals. Inhibition of dynamin, which interacts with Itsn1 during endocytosis, had no effect on STD recovery. Interestingly, we found a developmental enrichment of Itsn1 near VGCCs, which may underlie the Itsn1‐mediated fast replenishment of the RRP. Consequently, the absence of Itsn1 in mature synapses led to a higher failure rate of postsynaptic spiking during high‐frequency synaptic transmission. Taken together, our findings suggest that Itsn1 translocation to the vicinity of VGCCs during development is crucial for accelerating Ca2+‐dependent RRP replenishment and sustaining high‐fidelity neurotransmission. Itsn1 is expressed in the pre‐ and postsynaptic compartments of the calyx of Held synapse. Developmental upregulation of vesicular glutamate transporter‐1 is Itsn1 dependent. Itsn1 does not affect basal synaptic transmission at different developmental stages. Itsn1 is required for Ca2+‐dependent recovery from short‐term depression in mature synapses. Itsn1 mediates the recovery through its DH–PH domains, independent of its interactive partner dynamin. Itsn1 translocates to the vicinity of presynaptic Ca2+ channels during development. Itsn1 supports high‐fidelity neurotransmission by enabling rapid recovery from vesicular depletion during repetitive activity. [ABSTRACT FROM AUTHOR]

Synapses are organized into nanocolumns that control synaptic transmission efficacy through precise alignment of postsynaptic neurotransmitter receptors and presynaptic release sites. Recent evidence show that Leucine-Rich Repeat Transmembrane protein LRRTM2, highly enriched and confined at synapses, interacts with Neurexins through its C-terminal cap, but the role of this binding interface has not been explored in synapse formation and function. Here, we develop a conditional knock-out mouse model (cKO) to address the molecular mechanisms of LRRTM2 regulation, and its role in synapse organization and function. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function in mice. Surface expression, synaptic clustering, and membrane dynamics of LRRTM2 are tightly controlled by selective motifs in the C-terminal domain. Conversely, the N-terminal domain controls presynapse nano-organization and postsynapse AMPAR sub-positioning and stabilization through the recently identified Neurexin-binding interface. Thus, we identify LRRTM2 as a central organizer of pre- and post- excitatory synapse nanostructure through interaction with presynaptic Neurexins. Synapse nanocolumns control neural transmission through precise alignment of neurotransmitter receptors and release sites. Here, the authors identify the Neurexin-LRRTM2 complex as a central organiser of excitatory synapse nanostructure and function. [ABSTRACT FROM AUTHOR]

Acute traumatic event exposure is a direct cause of post-traumatic stress disorder (PTSD). Amygdala is suggested to be associated with the development of PTSD. In our previous findings, different activation patterns of GABAergic neurons and glutamatergic neurons in early or late stages after stress were found. However, the neural plastic mechanism underlying the role of basolateral amygdala (BLA) in post-traumatic stress disorder remains unclear. Therefore, this study mainly aimed at investigating time-dependent morphologic and electrophysiological changes in BLA during the development of PTSD. We used single prolonged stress (SPS) procedure to establish PTSD model of rats. The rats showed no alterations in anxiety behavior as well as in dendritic spine density or synaptic transmission in BLA 1 day after SPS. However, 10 days after SPS, rats showed enhancement of anxiety behavior, and spine density and frequency of miniature excitatory and inhibitory postsynaptic currents in BLA. Our results suggested that after traumatic stress, BLA displayed delayed increase in both spinogenesis and synaptic transmission, which seemed to facilitate the development of PTSD. [ABSTRACT FROM AUTHOR]

The critical brain hypothesis states that the brain can benefit from operating close to a second-order phase transition. While it has been shown that several computational aspects of sensory processing (e.g., sensitivity to input) can be optimal in this regime, it is still unclear whether these computational benefits of criticality can be leveraged by neural systems performing behaviorally relevant computations. To address this question, we investigate signatures of criticality in networks optimized to perform efficient coding. We consider a spike-coding network of leaky integrateand-fire neurons with synaptic transmission delays. Previously, it was shown that the performance of such networks varies nonmonotonically with the noise amplitude. Interestingly, we find that in the vicinity of the optimal noise level for efficient coding, the network dynamics exhibit some signatures of criticality, namely, scale-free dynamics of the spiking and the presence of crackling noise relation. Our work suggests that two influential, and previously disparate theories of neural processing optimization (efficient coding and criticality) may be intimately related. [ABSTRACT FROM AUTHOR]

Aging‐related decline in memory and synaptic function are associated with the dysregulation of calcium homeostasis, attributed to the overexpression of voltage‐gated calcium channels (VGCC). The membrane insertion of AMPAR governed by the AMPAR auxiliary proteins is essential for synaptic transmission and plasticity (LTP). In this study, we demonstrated the hippocampal expression of the transmembrane AMPAR regulatory proteins γ‐8 (TARPγ8) was reduced in aged mice along with the reduced CaMKIIα activity and memory impairment. We further showed that TARPγ8 expression was dependent on CaMKIIα activity. Inhibition of CaMKIIα activity significantly reduced the hippocampal TARPγ8 expression and CA3‐CA1 LTP in young mice to a similar level to that of the aged mice. Furthermore, the knockdown of hippocampal TARPγ8 impaired LTP and memory in young mice, which mimicked the aging‐related changes. We confirmed the enhanced hippocampal VGCC (Cav‐1.3) expression in aged mice and found that inhibition of VGCC activity largely increased both p‐CaMKIIα and TARPγ8 expression in aged mice, whereas inhibition of NMDAR or Calpains had no effect. In addition, we found that the exogenous expression of human TARPγ8 in the hippocampus in aged mice restored LTP and memory function. Collectively, these results indicate that the synaptic and cognitive impairment in aging is associated with the downregulation of CaMKIIα‐TARPγ8 signaling caused by VGCC activation. Our results suggest that TARPγ8 may be a key molecular biomarker for brain aging and that boosting CaMKIIα‐TARPγ8 signaling may be critical for the restoration of synaptic plasticity of aging and aging‐related diseases. [ABSTRACT FROM AUTHOR]

There is evidence that astrocytes modulate synaptic transmission in the nucleus tractus solitarius (NTS) interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations, we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of control and rats exposed to sustained hypoxia (SH). Baseline autonomic and respiratory activities and the responses to chemoreflex activation (KCN) were evaluated before and after microinjections of fluorocitrate (FCt, an astrocyte metabolic inhibitor), kynurenic acid, and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate (PPADS) (nonselective antagonists of glutamatergic and purinergic receptors) into the rostral aspect of the caudal commissural NTS. FCt had no effects on the baseline parameters evaluated but reduced the bradycardic response to chemoreflex activation in SH rats. FCt combined with kynurenic acid and PPADS in control rats reduced the baseline duration of expiration, which was attenuated after SH. FCt produced a large increase in PN frequency discharge in control rats, which was reduced after SH, indicating a reduction in the astrocyte modulation after SH. The data show that 1) the bradycardic component of the peripheral chemoreflex is reduced in SH rats after astrocytes inhibition, 2) the inhibition of astrocytes in the presence of double antagonists in the NTS affects the modulation of baseline duration of expiration in control but not in SH rats, and 3) the autonomic and respiratory responses to chemoreflex activation are mediated by glutamatergic and purinergic receptors in the rostral aspect of the caudal commissural NTS. NEW & NOTEWORTHY: Our findings indicate that the neurotransmission of autonomic and respiratory components of the peripheral chemoreflex in the nucleus tractus solitarius (NTS) is mediated by glutamatergic and purinergic mechanisms and reveal a selective involvement of NTS astrocytes in controlling the chemoreflex parasympathetic response in rats exposed to sustained hypoxia (SH) and the baseline duration of expiration mainly in control rats, indicating a selective role for astrocytes modulation in the NTS of control and SH rats. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a core feature of schizophrenia, playing a pivotal role in the pathogenesis and prognosis of this disorder. Cognitive impairment in schizophrenia encompasses a wide range of domains, including processing speed, episodic memory, working memory, and executive function. These deficits persist throughout the course of the illness and significantly impact functional outcomes and quality of life. Therefore, it is imperative to identify the biological basis of cognitive deficits in schizophrenia and develop effective treatments. The role of N-methyl-D-aspartate (NMDA) receptors in synaptic transmission and plasticity has long been recognized, making them potential targets for schizophrenia treatment. This review will focus on emerging pharmacology targeting NMDA receptors, offering strategies for the prevention and treatment of cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Improved genetically encoded calcium indicators (GECIs) are essential for capturing intracellular dynamics of both muscle and neurons. A novel set of GECIs with ultrafast kinetics and high sensitivity was recently reported by Zhang et al. (2023). While these indicators, called jGCaMP8, were demonstrated to work in Drosophila and mice, data for Caenorhabditis elegans were not reported. Here, we present an optimized construct for C. elegans and use this to generate several strains expressing GCaMP8f (fast variant of the indicator). Utilizing the myo-2 promoter, we compare pharyngeal muscle activity measured with GCaMP7f and GCaMP8f and find that GCaMP8f is brighter upon binding to calcium, shows faster kinetics, and is not disruptive to the intrinsic contraction dynamics of the pharynx. Additionally, we validate its application for detecting neuronal activity in touch receptor neurons which reveals robust calcium transients even at small stimulus amplitudes. As such, we establish GCaMP8f as a potent tool for C. elegans research which is capable of extracting fast calcium dynamics at very low magnifications across multiple cell types. [ABSTRACT FROM AUTHOR]

For a subset of individuals known as sign‐trackers, discrete Pavlovian cues associated with rewarding stimuli can acquire incentive properties and exert control over behaviour. Because responsiveness to cues is a feature of various neuropsychiatric conditions, rodent models of sign‐tracking may prove useful for exploring the neurobiology of individual variation in psychiatric vulnerabilities. Converging evidence points towards the involvement of dopaminergic neurotransmission in the nucleus accumbens core (NAc) in the development of sign‐tracking, yet whether this phenotype is associated with specific accumbal postsynaptic properties is unknown. Here, we examined dendritic spine structural organisation, as well as presynaptic and postsynaptic markers of activity, in the NAc core of male and female rats following a Pavlovian‐conditioned approach procedure. In contrast to our prediction that cue re‐exposure would increase spine density, experiencing the discrete lever‐cue without reward delivery resulted in lower spine density than control rats for which the lever was unpaired with reward during training; this effect was tempered in the most robust sign‐trackers. Interestingly, this same behavioural test (lever presentation without reward) resulted in increased levels of a marker of presynaptic activity (synaptophysin), and this effect was greatest in female rats. Whilst some behavioural differences were observed in females during initial Pavlovian training, final conditioning scores did not differ from males and were unaffected by the oestrous cycle. This work provides novel insights into how conditioning impacts the neuronal plasticity of the NAc core, whilst highlighting the importance of studying the behaviour and neurobiology of both male and female rats. [ABSTRACT FROM AUTHOR]

Sleep/wake cycles intricately shape physiological activities including cognitive brain functions, yet the precise molecular orchestrators of sleep remain elusive. Notably, the clinical impact of benzodiazepine drugs underscores the pivotal role of GABAergic neurotransmission in sleep regulation. However, the specific contributions of distinct GABAA receptor subtypes and their principal scaffolding protein, gephyrin, in sleep dynamics remain unclear. The evolving role of synaptic phospho‐proteome alterations at excitatory and inhibitory synapses suggests a potential avenue for modulating gephyrin and, consequently, GABAARs for sleep through on‐demand kinase recruitment. Our study unveils the distinctive roles of two prevalent GABAA receptor subtypes, α1‐ and α2‐GABAARs, in influencing sleep duration and electrical sleep activity. Notably, the absence of α1‐GABAARs emerges as central in sleep regulation, manifesting significant alterations in both non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep during dark or active phases, accompanied by altered electroencephalogram (EEG) patterns across various frequencies. Gephyrin proteomics analysis reveals sleep/wake‐dependent interactions with a repertoire of known and novel kinases. Crucially, we identify the regulation of gephyrin interaction with ERK1/2, and phosphorylations at serines 268 and 270 are dictated by sleep/wake cycles. Employing AAV‐eGFP‐gephyrin or its phospho‐null variant (S268A/S270A), we disrupt sleep either globally or locally to demonstrate gephyrin phosphorylation as a sleep regulator. In summary, our findings support the local cortical sleep hypothesis and we unveil a molecular mechanism operating at GABAergic synapses, providing critical insights into the intricate regulation of sleep. [ABSTRACT FROM AUTHOR]

The anterior cingulate cortex (ACC) is one of the critical brain areas for processing noxious information. Previous studies showed that peripheral nerve injury induced broad changes in the ACC, contributing to pain hypersensitivity. The neurons in layer 3 (L3) of the ACC receive the inputs from the mediodorsal thalamus (MD) and form the feedforward inhibition (FFI) microcircuits. The effects of peripheral nerve injury on the MD-driven FFI in L3 of ACC are unknown. In our study, we record the enhanced excitatory synaptic transmissions from the MD to L3 of the ACC in mice with common peroneal nerve ligation, affecting FFI. Chemogenetically activating the MD-to-ACC projections induces pain sensitivity and place aversion in naive mice. Furthermore, chemogenetically inactivating MD-to-ACC projections decreases pain sensitivity and promotes place preference in nerve-injured mice. Our results indicate that the peripheral nerve injury changes the MD-to-ACC projections, contributing to pain hypersensitivity and aversion. Injury-induced changes in MD-to-L3 projections, leading to increased feed forward inhibition, contribute to both pain aversion and altered pain thresholds. Manipulating these inputs affects pain-related behaviors, highlighting their role in pathological pain. [ABSTRACT FROM AUTHOR]

Ubiquitin ligases are important regulators of nervous system development, function and disease. To date, numerous ubiquitin ligases have been discovered that regulate presynaptic biology. Here, we discuss recent findings on presynaptic ubiquitin ligases that include members from the three major ubiquitin ligase classes: RING, RBR and HECT. Several themes emerge based on findings across a range of model systems. A cadre of ubiquitin ligases is required presynaptically to orchestrate development and transmission at synapses. Multiple ubiquitin ligases deploy both enzymatic and non‐enzymatic mechanisms, and act as hubs for signalling networks at the synapse. Both excitatory and inhibitory presynaptic terminals are influenced by ligase activity. Finally, there are several neurodevelopmental disorders and neurodegenerative diseases associated with presynaptic ubiquitin ligases. These findings highlight the growing prominence and biomedical relevance of the presynaptic ubiquitin ligase network. [ABSTRACT FROM AUTHOR]

Neuropsychiatric and neurological disorders pose a significant global health burden, highlighting the need for innovative therapeutic approaches. Fingolimod (FTY720), a common drug to treat multiple sclerosis, has shown promising efficacy against various neuropsychiatric and neurological disorders. Fingolimod exerts its neuroprotective effects by targeting multiple cellular and molecular processes, such as apoptosis, oxidative stress, neuroinflammation, and autophagy. By modulating Sphingosine-1-Phosphate Receptor activity, a key regulator of immune cell trafficking and neuronal function, it also affects synaptic activity and strengthens memory formation. In the hippocampus, fingolimod decreases glutamate levels and increases GABA levels, suggesting a potential role in modulating synaptic transmission and neuronal excitability. Taken together, fingolimod has emerged as a promising neuroprotective agent for neuropsychiatric and neurological disorders. Its broad spectrum of cellular and molecular effects, including the modulation of apoptosis, oxidative stress, neuroinflammation, autophagy, and synaptic plasticity, provides a comprehensive therapeutic approach for these debilitating conditions. Further research is warranted to fully elucidate the mechanisms of action of fingolimod and optimize its use in the treatment of neuropsychiatric and neurological disorders. [ABSTRACT FROM AUTHOR]

For animals to meet environmental challenges, the activity patterns of specialized oscillatory neural circuits, central pattern generators (CPGs), controlling rhythmic movements like breathing and locomotion, are adjusted by neuromodulation. As a representative example, the leech heartbeat is controlled by a CPG driven by two pairs of mutually inhibitory interneurons, heart interneuron (HN) half-center oscillators (HCO). Experiments and modeling indicate that neuromodulation of HCO navigates this CPG between dysfunctional regimes by employing a co-regulating inverted relation; reducing Na+/K+ pump current and increasing hyperpolarization-activated (h-) current. Simply reducing pump activity or increasing h-current leads to either seizure-like bursting or an asymmetric bursting dysfunctional regime, respectively. Here, we demonstrate through modeling that, alongside this coregulation path, a new bursting regime emerges. Both regimes fulfill the criteria for functional bursting activity. Although the cycle periods and burst durations of these patterns are roughly the same, the new one exhibits an intra-burst spike frequency that is twice as high as the other. This finding suggests that neuromodulation could introduce additional functional regimes with higher spike frequency, and thus more effective synaptic transmission to motor neurons. We found that this new regime co-exists with the original bursting. The HCO can be switched between them by a short pulse of excitatory or inhibitory conductance. In this domain of coexisting functional patterns, an isolated cell model exhibits only one regime, a severely dysfunctional plateau-containing, seizure-like activity. This aligns with widely reported notion that deficiency of inhibition can cause seizures and other dysfunctional neural activities. We show that along the coregulation path of neuromodulation, the high excitability of the single HNs induced by myomodulin is harnessed by mutually inhibitory synaptic interactions of the HCO into the functional bursting pattern. [ABSTRACT FROM AUTHOR]

Disruptions in glutamate homeostasis within the mesolimbic reward circuitry may play a role in the pathophysiology of various reward related disorders such as major depressive disorders, anxiety, and substance use disorders. Clear sex differences have emerged in the rates and symptom severity of these disorders which may result from differing underlying mechanisms of glutamatergic signaling. Indeed, preclinical models have begun to uncover baseline sex differences throughout the brain in glutamate transmission and synaptic plasticity. Glutamatergic synaptic strength can be assessed by looking at morphological features of glutamatergic neurons including spine size, spine density, and dendritic branching. Likewise, electrophysiology studies evaluate properties of glutamatergic neurons to provide information of their functional capacity. In combination with measures of glutamatergic transmission, synaptic plasticity can be evaluated using protocols that induce long-term potentiation or long-term depression. This review will consider preclinical rodent literature directly comparing glutamatergic transmission and plasticity in reward related regions of males and females. Additionally, we will suggest which regions are exhibiting evidence for sexually dimorphic mechanisms, convergent mechanisms, or no sex differences in glutamatergic transmission and plasticity and highlight gaps in the literature for future investigation. [ABSTRACT FROM AUTHOR]

Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (Aβ)-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Detection and analysis of spontaneous synaptic events is an extremely common task inmany neuroscience research labs. Various algorithms and tools have been developed over the years to improve the sensitivity of detecting synaptic events. However, the final stages of most procedures for detecting synaptic events still involve the manual selection of candidate events. This step in the analysis is laborious and requires care and attention to maintain consistency of event selection across the whole dataset. Manual selection can introduce bias and subjective selection criteria that cannot be shared with other labs in reporting methods. To address this, we have created Eventer, a standalone application for the detection of spontaneous synaptic events acquired by electrophysiology or imaging. This open-source application uses the freely available MATLAB Runtime and is deployed on Mac, Windows, and Linux systems. The principle of the Eventer application is to learn the user's "expert" strategy for classifying a set of detected event candidates from a small subset of the data and then automatically apply the same criterion to the remaining dataset. Eventer first uses a suitable model template to pull out event candidates using fast Fourier transform (FFT)-based deconvolution with a low threshold. Random forests are then created and trained to associate various features of the events with manual labeling. The storedmodel file can be reloaded and used to analyse large datasets with greater consistency. The availability of the source code and its user interface provide a framework with the scope to further tune the existing Random Forest implementation, or add additional, artificial intelligence classification methods. The Eventer website (https://eventerneuro.netlify.app/) includes a repository where researchers can upload and share their machine learning model files and thereby provide greater opportunities for enhancing reproducibility when analyzing datasets of spontaneous synaptic activity. In summary, Eventer, and the associated repository, could allow researchers studying synaptic transmission to increase throughput of their data analysis and address the increasing concerns of reproducibility in neuroscience research. [ABSTRACT FROM AUTHOR]

The microtubule‐associated protein tau participates in neurotransmission regulation via its interaction with synaptic vesicles (SVs). The precise nature and mechanics of tau's engagement with SVs, especially regarding alterations in vesicle dynamics, remain a matter of discussion. We report an electrochemical method using a synapse‐mimicking nanopipette to monitor vesicle dynamics induced by tau. A model vesicle of ~30 nm is confined within a lipid‐modified nanopipette orifice with a comparable diameter to mimic the synaptic lipid environment. Both tau and phosphorylated tau (p‐tau) present two‐state dynamic behavior in this biomimetic system, showing typical ionic current oscillation, induced by lipid‐tau interaction. The results indicate that p‐tau has a stronger affinity to the lipid vesicles in the confined environment, blocking the vesicle movement to a higher degree. Taken together, this method bridges a gap for sensing synaptic vesicle dynamics in a confined lipid environment, mimicking vesicle movement near the synaptic membrane. These findings contribute to understanding how different types of tau protein regulate synaptic vesicle motility and to underlying its functional and pathological behaviours in disease. [ABSTRACT FROM AUTHOR]

The Venus flytrap sea anemone Actinoscyphia liui inhabits the nutrient‐limited deep ocean in the tropical western Pacific. Compared with most other sea anemones, it has undergone a distinct modification of body shape similar to that of the botanic flytrap. However, the molecular mechanism by which such a peculiar sea anemone adapts to a deep‐sea oligotrophic environment is unknown. Here, we report the chromosomal‐level genome of A. liui constructed from PacBio and Hi‐C data. The assembled genome is 522 Mb in size and exhibits a continuous scaffold N50 of 58.4 Mb. Different from most other sea anemones, which typically possess 14–18 chromosomes per haplotype, A. liui has only 11. The reduced number of chromosomes is associated with chromosome fusion, which likely represents an adaptive strategy to economize energy in oligotrophic deep‐sea environments. Comparative analysis with other deep‐sea sea anemones revealed adaptive evolution in genes related to cellular autophagy (TMBIM6, SESN1, SCOCB and RPTOR) and mitochondrial energy metabolism (MDH1B and KAD2), which may aid in A. liui coping with severe food scarcity. Meanwhile, the genome has undergone at least two rounds of expansion in gene families associated with fast synaptic transmission, facilitating rapid responses to water currents and prey. Positive selection was detected on putative phosphorylation sites of muscle contraction‐related proteins, possibly further improving feeding efficiency. Overall, the present study provides insights into the molecular adaptation to deep‐sea oligotrophic environments and sheds light upon potential effects of a novel morphology on the evolution of Cnidaria. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is the most common inherited disorder of amino acid metabolism, characterized by high levels of phenylalanine (Phe) in the blood and brain, leading to cognitive impairment without treatment. Nevertheless, Phe-mediated brain dysfunction is not fully understood. The objective of this study was to address gene expression alterations due to excessive Phe exposure in the human neuronal model and provide molecular advances in PKU pathophysiology. Hence, we performed NT2/D1 differentiation in culture, and, for the first time, we used Phe-treated NT2-derived neurons (NT2/N) as a novel model for Phe-mediated neuronal impairment. NT2/N were treated with 1.25 mM, 2.5 mM, 5 mM, 10 mM, and 30 mM Phe and subjected to whole-mRNA short-read sequencing. Differentially expressed genes (DEGs) were analyzed and enrichment analysis was performed. Under three different Phe concentrations (2.5 mM, 5 mM, and 10 mM), DEGs pointed to the PREX1, LRP4, CDC42BPG, GPR50, PRMT8, RASGRF2, and CDH6 genes, placing them in the context of PKU for the first time. Enriched processes included dendrite and axon impairment, synaptic transmission, and membrane assembly. In contrast to these groups, the 30 mM Phe treatment group clearly represented the neurotoxicity of Phe, exhibiting enrichment in apoptotic pathways. In conclusion, we established NT2/N as a novel model for Phe-mediated neuronal dysfunction and outlined the Phe-induced gene expression changes resulting in neurite impairment and altered synaptic connectivity. [ABSTRACT FROM AUTHOR]

Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident. [ABSTRACT FROM AUTHOR]

Background: Reduction of the production of amyloid-β (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored. Objective: To investigate the potential of multi-copper oxidases (MCOs) in degrading Aβ peptides and their potential benefits for AD treatment. Methods: We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aβ interaction using total internal reflection fluorescence microscopy, fluorescence photometer, and fluorescence polarization measurement. We also investigated the therapeutic effect of ascorbate oxidase (AO) by using induced pluripotent stem (iPS) neuron cells and electrophysiological analysis with brain slices. Results: We discovered that CP, an important MCO in human blood, could degrade Aβ peptides. We also found that other MCOs could induce Aβ degradation as well. Remarkably, we revealed that AO had the strongest degrading effect among the tested MCOs. Using iPS neuron cells, we observed that AO could rescue neuron toxicity which induced by Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. Conclusions: To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD. [ABSTRACT FROM AUTHOR]

Neuroligin-2 (Nlgn2) is a key synaptic adhesion protein at virtually all GABAergic synapses, which recruits GABAARs by promoting assembly of the postsynaptic gephyrin scaffold. Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interactors and redundancies define its function, but the nature of these interactions remain poorly understood. Here we investigated how Nlgn2 function in hippocampal area CA1 is modulated by two proposed interaction partners, MDGA1 and MDGA2. We show that loss of MDGA1 expression, but not heterozygous deletion of MDGA2, ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behaviour characterizing Nlgn2 knockout (KO) mice. Additionally, combined Nlgn2 and MDGA1 deletion causes an exacerbated layer-specific loss of gephyrin puncta. Given that both Nlgn2 and the MDGA1 have been correlated with many psychiatric disorders, our data support the notion that cytosolic gephyrin aggregation may represent an interesting target for novel therapeutic strategies. Analysis of inhibitory synapses in mouse hippocampus uncovers functional interactions between postsynaptic organizer proteins Neuroligin-2 and MDGA1 in regulating gephyrin aggregation, GABAergic synaptic transmission, and behavior. [ABSTRACT FROM AUTHOR]

Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S‐nitrosylation of gephyrin (SNO‐gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO‐gephyrin is significantly increased in the BLA of high‐anxiety rats and a downregulation of SNO‐gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO‐gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABAAR γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic‐like effects of physical exercise. This study reveals a key role of downregulating SNO‐gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post‐translational modifications in the brain after exercise. [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]

Synaptic communication is an important process in the central nervous system that allows for the rapid and spatially specified transfer of signals. Neurons receive various synaptic inputs and generate action potentials required for information transfer, and these inputs can be excitatory or inhibitory, which collectively determines the output. Non-neuronal cells (glial cells) have been identified as crucial participants in influencing neuronal activity and synaptic transmission, with astrocytes forming tripartite synapses and microglia pruning synapses. While it has been known that oligodendrocyte precursor cells (OPCs) receive neuronal inputs, whether they also influence neuronal activity and synaptic transmission has remained unknown for two decades. Recent findings indicate that OPCs, too, modulate neuronal synapses. In this review, we discuss the roles of different glial cell types at synapses, including the recently discovered involvement of OPCs in synaptic transmission and synapse refinement, and discuss overlapping roles played by multiple glial cell types. [ABSTRACT FROM AUTHOR]

Background: Particulate matter with a diameter of < 2.5 μm (PM2.5) influences gene regulation via DNA methylation; however, its precise mechanism of action remains unclear. Thus, this study aimed to examine the connection between personal PM2.5 exposure and DNA methylation in CpG islands as well as explore the associated gene pathways. Methods: A total of 95 male patients with chronic obstructive pulmonary disease (COPD) were enrolled in this study. PM2.5 concentrations were measured for 12 months, with individual exposure recorded for 24 h every 3 months. Mean indoor and estimated individual PM2.5 exposure levels were calculated for short-term (7 days), mid-term (35 days), and long-term (90 days). DNA methylation analysis was performed on the blood samples, which, after PCR amplification and hybridization, were finally sequenced using an Illumina NovaSeq 6000 system. Correlation between PM2.5 exposure and CpG methylation sites was confirmed via a mixed-effects model. Functional enrichment analysis was performed on unique CpG methylation sites associated with PM2.5 exposure to identify the relevant biological functions or pathways. Results: The number of CpG sites showing differential methylation was 36, 381, and 182 for the short-, mid-, and long-term indoor models, respectively, and 3, 98, and 28 for the short-, mid-, and long-term estimated exposure models, respectively. The representative genes were TMTC2 (p = 1.63 × 10-3, R2 = 0.656), GLRX3 (p = 1.46 × 10-3, R2 = 0.623), DCAF15 (p = 2.43 × 10-4, R2 = 0.623), CNOT6L (p = 1.46 × 10-4, R2 = 0.609), BSN (p = 2.21 × 10-5, R2 = 0.606), and SENP6 (p = 1.59 × 10-4, R2 = 0.604). Functional enrichment analysis demonstrated that the related genes were mostly associated with pathways related to synaptic transmission in neurodegenerative diseases and cancer. Conclusion: A significant association was observed between PM2.5 exposure and DNA methylation upon short-term exposure, and the extent of DNA methylation was the highest upon mid-term exposure. Additionally, various pathways related to neurodegenerative diseases and cancer were associated with patients with COPD. ClinicalTrials.gov identifier: NCT04878367. [ABSTRACT FROM AUTHOR]

Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long‐term potentiation (LTP1) into the stronger long‐lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long‐term memory. D3R effects were mainly mediated by post‐synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR‐mediated currents, mEPSC amplitude, and the expression of the post‐synaptic proteins PSD‐95, phospho(p)GluA1 and p‐CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post‐synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post‐synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post‐synaptic protein expression, and PSD length. Notably, aged D3‐KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age‐related hippocampal cognitive decline. [ABSTRACT FROM AUTHOR]

Throughout our evolutionary history, physical activity has played a significant role in shaping our physiology. Advances in exercise science have further reinforced this concept by highlighting how exercise can change gene expression and molecular signaling to achieve various beneficial outcomes. Several studies have shown that exercise can alter neuronal functions to prevent neurodegenerative conditions like Parkinson's and Alzheimer's diseases. However, individual genotypes, phenotypes, and varying exercise protocols hinder the prescription of exercise as standard therapy. Moreover, exercise-induced molecular signaling targets can be double-edged swords, making it difficult to use exercise as the primary candidate for beneficial effects. For example, activating PGC-1 alpha and BDNF through exercise could produce several benefits in maintaining brain health, such as plasticity, neuronal survival, memory formation, cognition, and synaptic transmission. However, higher expression of BDNF might playa negative role in bipolar disorder. Therefore, further understanding of a specific mechanistic approach is required. This review focuses on how exercise-induced activation of these molecules could support brain health and discusses the potential underlying mechanisms of the effect of exercise-induced PGC-1 alpha and BDNF on brain health. [ABSTRACT FROM AUTHOR]

Background and objectives: There is an urgent need to discover blood-based biomarkers of multiple sclerosis (MS) to better define the underlying biology of relapses and monitor disease progression. The main goal of this study is to search for candidate biomarkers of MS relapses associated with circulating extracellular vesicles (EVs), an emerging tool for biomarker discovery. Methods: EVs, purified from unpaired plasma and CSF samples of RRMS patients by size-exclusion chromatography (SEC), underwent proteomic analysis to discover novel biomarkers associated with MS relapses. The candidate biomarkers of disease activity were detected by comparison approach between plasma- and CSF-EV proteomes associated with relapses. Among them, a selected potential biomarker was evaluated in a cohort of MS patients, using a novel and highly reproducible flow cytometry-based approach in order to detect low abundant EV subsets in a complex body fluid such as plasma. Results: The proteomic profiles of both SEC-purified plasma EVs (from 6 patients in relapse and 5 patients in remission) and SEC-purified CSF EVs (from 4 patients in relapse and 3 patients in remission) revealed a set of proteins associated with MS relapses significant enriched in the synaptic transmission pathway. Among common proteins, excitatory amino-acid transporter 2, EAAT2, responsible for the majority of the glutamate uptake in CNS, was worthy of further investigation. By screening plasma samples from 110 MS patients, we found a significant association of plasma EV-carried EAAT2 protein (EV-EAAT2) with MS relapses, regardless of disease-modifying therapies. This finding was confirmed by investigating the presence of EV-EAAT2 in plasma samples collected longitudinally from 10 RRMS patients, during relapse and remission. Moreover, plasma EV-EAAT2 levels correlated positively with Expanded Disability Status Scale (EDSS) score in remitting MS patients but showed a negative correlation with age in patients with secondary progressive (SPMS). Conclusion: Our results emphaticize the usefulness of plasma EVs as a source of accessible biomarkers to remotely analyse the CNS status. Plasma EV-EAAT2 showed to be a promising biomarker for MS relapses. Further studies are required to assess the clinical relevance of this biomarker also for disability progression independent of relapse activity and transition from RRMS towards SPMS. [ABSTRACT FROM AUTHOR]

FKBP51, also known as FK506‐binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub‐anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel‐running activity, but did offer protection against stress‐mediated disruptions in rhythmicity in a sex‐dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region‐ and sex‐dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal‐cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51‐focused therapeutics for stress‐related disorders. [ABSTRACT FROM AUTHOR]

Neuroprotection aims to safeguard neurons from damage caused by various factors like stress, potentially leading to the rescue, recovery, or regeneration of the nervous system and its functions [J Clin Neurosci. 2002;9(1):4–8]. Conversely, neuroplasticity refers to the brain's ability to adapt and change throughout life, involving structural and functional alterations in cells and synaptic transmission [Neural Plast. 2014;2014:541870]. Neuroprotection is a broad and multidisciplinary field encompassing various approaches and strategies aimed at preserving and promoting neuronal health. It is a critical area of research in neuroscience and neurology, with the potential to lead to new therapies for a wide range of neurological disorders and conditions. Neuroprotection can take various forms and may involve pharmacological agents, lifestyle modifications, or behavioral interventions. Accordingly, also the perspective and the meaning of neuroprotection differs due to different angles of interpretation. The primary interpretation is from the pharmacological point of view since the most consistent data come from this field. In addition, we will discuss also alternative, yet less considered, perspectives on neuroprotection, focusing on specific neuroprotective targets, interactions with surrounding microglia, different levels of neuroprotective effects, the reversive/adaptative dimension, and its use as anticipatory/prophylactic intervention. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are characterized by progressive dysfunction and loss of specific sets of neurons. While extensive research has focused on elucidating the genetic and epigenetic factors and molecular mechanisms underlying these disorders, emerging evidence highlights the critical role of secretion in the pathogenesis, possibly even onset, and progression of neurodegenerative diseases, suggesting the occurrence of non-cell-autonomous mechanisms. Secretion is a fundamental process that regulates intercellular communication, supports cellular homeostasis, and orchestrates various physiological functions in the body. Defective secretion can impair the release of neurotransmitters and other signaling molecules, disrupting synaptic transmission and compromising neuronal survival. It can also contribute to the accumulation, misfolding, and aggregation of disease-associated proteins, leading to neurotoxicity and neuronal dysfunction. In this review, we discuss the implications of defective secretion in the context of Parkinson’s disease, emphasizing its role in protein aggregation, synaptic dysfunction, extracellular vesicle secretion, and neuroinflammation. We propose a multiple-hit model whereby protein accumulation and secretory defects must be combined for the onset and progression of the disease. [ABSTRACT FROM AUTHOR]

Following exocytosis, the recapture of plasma membrane‐stranded vesicular proteins into recycling synaptic vesicles (SVs) is essential for sustaining neurotransmission. Surface clustering of vesicular proteins has been proposed to act as a 'pre‐assembly' mechanism for endocytosis that ensures high‐fidelity retrieval of SV cargo. Here, we used single‐molecule imaging to examine the nanoclustering of synaptotagmin‐1 (Syt1) and synaptic vesicle protein 2A (SV2A) in hippocampal neurons. Syt1 forms surface nanoclusters through the interaction of its C2B domain with SV2A, which are sensitive to mutations in this domain (Syt1K326A/K328A) and SV2A knockdown. SV2A co‐clustering with Syt1 is reduced by blocking SV2A's cognate interaction with Syt1 (SV2AT84A). Surprisingly, impairing SV2A‐Syt1 nanoclustering enhanced the plasma membrane recruitment of key endocytic protein dynamin‐1, causing accelerated Syt1 endocytosis, altered intracellular sorting and decreased trafficking of Syt1 to Rab5‐positive endocytic compartments. Therefore, SV2A and Syt1 are segregated from the endocytic machinery in surface nanoclusters, limiting dynamin recruitment and negatively regulating Syt1 entry into recycling SVs. [ABSTRACT FROM AUTHOR]

The regulation of dopamine (DA) removal from the synaptic cleft is a crucial process in neurotransmission and is facilitated by the sodium‐ and chloride‐coupled dopamine transporter DAT. Psychostimulant drugs, cocaine, and amphetamine, both block the uptake of DA, while amphetamine also triggers the release of DA. As a result, they prolong or even amplify neurotransmitter signaling. Atypical inhibitors of DAT lack cocaine‐like rewarding effects and offer a promising strategy for the treatment of drug use disorders. Here, we present the 3.2 Å resolution cryo‐electron microscopy structure of the Drosophila melanogaster dopamine transporter (dDAT) in complex with the atypical non‐competitive inhibitor AC‐4‐248. The inhibitor partially binds at the central binding site, extending into the extracellular vestibule, and locks the transporter in an outward open conformation. Our findings propose mechanisms for the non‐competitive inhibition of DAT and attenuation of cocaine potency by AC‐4‐248 and provide a basis for the rational design of more efficacious atypical inhibitors. [ABSTRACT FROM AUTHOR]