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Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.

Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder.

Background: Oxidative stress plays a major role in Alzheimer’s disease (AD) pathogenesis, and thus, antioxidant glutathione (GSH) has been actively investigated in mitigating the oxidative load. Significant hippocampal GSH depletion has been correlated with cognitive impairment in AD. Furthermore, postmortem studies indicated alterations in cellular-energy metabolism and hippocampal pH change toward alkalinity in AD. Objective: Concurrent analysis of hippocampal GSH and pH interplay in vivo on the same individual is quite unclear and hence requires investigation to understand the pathological events in AD. Methods: Total 39 healthy old (HO), 22 mild cognitive impairment (MCI), and 37 AD patients were recruited for hippocampal GSH using 1H-MRS MEGA-PRESS and pH using 2D 31P-MRSI with dual tuned (1H/31P) transmit/receive volume head coil on 3T-Philips scanner. All MRS data processing using KALPANA package and statistical analysis were performed MedCalc, respectively and NINS-STAT package. Results: Significant GSH depletion in the left and right hippocampus (LH and RH) among MCI and AD study groups as compared to HO was observed, whereas pH increased significantly in the LH region between HO and AD. Hippocampal GSH level negatively correlated with pH in both patient groups. The ROC analysis on the combined effect of GSH and pH in both hippocampal regions give accuracy for MCI (LH: 78.27%; RH: 86.96%) and AD (LH: 88%; RH: 78.26%) groups differentiating from HO. Conclusion: Outcomes from this study provide further insights to metabolic alterations in terms of concurrent assessment of hippocampal GSH and pH levels in AD pathogenesis, aiding in early diagnosis of MCI and AD.

Objective After 160 years the true underlying cause of Meniere's disease remains enigmatic. The aim of our study is to discuss the possible implication of an obstruction of the ductus reuniens as a cause in Meniere's disease. Methodology We first conducted an historical study of the description of the ductus reuniens. We then reviewed the literature regarding ductus reuniens obstruction in animal experiments, human post-mortem studies and living ear imaging. We completed its description by modern microCT imaging. Limited knowledge on the fate of dislodged saccular otoconia is summarized. The possible implications for Meniere's attacks are discussed. Results Victor Hensen was the first to describe the ductus reuniens in 1863. He described its length and width and predicted that saccular otoconia might enter the ductus and the cochlea. On microCT the narrowest width of the human ductus reuniens was 0.14 mm. The literature reports cochlear endolymphatic hydrops occurring after animal experimental obstruction of the duct. Human postmortem studies have confirmed saccular otoconial clumps entering the ductus and the cochlea. A postmortem study has shown sites of endolymphatic obstruction, and imaging speculates on blockages in ears with Meniere's disease. Dislodged utricular otoconia can be in clumps of otolithic membranes. Conclusion Blockages of the ductus reuniens and at other endolymphatic system sites appear to be a feature in Meniere's disease ears. The blockages have been postulated to be saccular otoconia either causing or aggravating hydrops. This could be consistent with observed nystagmus reversals during attacks as the endolymphatic sac attempts to clear the hydrops and the otoconia.

Background: Performing identity is a prime task in medicolegal and postmortem examinations. Age is the first parameter that has to be determined followed by sex. There are several techniques through which sex can be determined. As well there are different anatomical, physiological and pathological parameters determination of sex. Aim: To determine the sexual dimorphism in the cranial sagittal suture closure macroscopically. Methods: All the cases for this purpose had been selected from those brought for autopsy in the Department of Forensic Medicine and Toxicology, King Edward Medical University Lahore during the year 2016. Results: The statistical analysis revealed early closure in males than in females both ectocranially and endocranially with advancing age in the sagittal suture of cranial vault. The p value was found significant being less than 0.05 thereby establishing the fact that sexual dimorphism in the cranial sagittal suture exists. Conclusion: Conclusively the determination of sex is possible from the pattern of Cranial Sutures closure on autopsy table. Key words: Sex, Sagittal, Suture, Cranial

The spreading of misfolded alpha-synuclein (α-syn) protein has been observed in animal models of Parkinson's disease (PD) and other α-synucleinopathies that mimic human PD pathologies. In animal models, the spreading of α-syn has been associated with motor dysfunction and neuronal death. However, variability in both susceptible brain regions and cellular populations limits our understanding of the consequences of α-syn spreading and the development of associated therapies. Here, we have reviewed the physiological and pathological functions of α-syn and summarized the susceptible brain regions and cell types identified from human postmortem studies and exogenous α-syn injection-based animal models. We have reviewed the methods for inducing α-syn aggregation, the specific hosts, the inoculation sites, the routes of propagation, and other experimental settings that may affect the spreading pattern of α-syn, as reported in current studies. Understanding the spread of α-syn to produce a consistent PD animal model is vital for future drug discovery.

Purpose Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX-2 subtype has been associated with inflammation, whereas the constitutively expressed COX-1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX-1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX-1. Methods Five databases were used to retrieve relevant studies that addressed COX-1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX-1 isoform under such conditions. Results Reviewed literature generally indicated that the overexpression of COX-1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX-1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX-1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX-1 in patients with Alzheimer's disease. Conclusion Taken together, studies in cultured cells and living rodents suggest that COX-1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX-1-expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX-1 in neuroinflammation in the living human brain is still largely lacking.

In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall markedly reduced relative to the non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved.

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

Background: Postmortem studies of brains with Alzheimer’s disease (AD) not only find amyloid-beta (Aβ) and neurofibrillary tangles (NFT) in the visual cortex, but also reveal temporally sequential changes in AD pathology from higher-order association areas to lower-order areas and then primary visual area (V1) with disease progression. Objective: This study investigated the effect of AD severity on visual functional network. Methods: Eight severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a resting-state fMRI (rs-fMRI) and a task fMRI of viewing face photos. A resting-state visual functional connectivity (FC) network and a face-evoked visual-processing network were identified for each group. Results: For the HS, the identified group-mean face-evoked visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, the resting-state visual FC network was mainly confined within the visual cortex. AD disrupted these two functional networks in a similar severity dependent manner: the more severe the cognitive impairment, the greater reduction in network connectivity. For the face-evoked visual-processing network, MAD disrupted and reduced activation mainly in the higher-order visual association areas, with SAD further disrupting and reducing activation in the lower-order areas. Conclusion: These findings provide a functional corollary to the canonical view of the temporally sequential advancement of AD pathology through visual cortical areas. The association of the disruption of functional networks, especially the face-evoked visual-processing network, with AD severity suggests a potential predictor or biomarker of AD progression.

OBJECTIVE The goal of this systematic review is to evaluate the association between fluid biomarkers and white matter hyperintensities (WMH) in cerebrovascular disease and neurodegenerative disorders. While previous research has examined the etiology of WMH in specific diseases, we propose a comprehensive framework encompassing WMH of both vascular and non-vascular origin. INTRODUCTION Although WMH have been mostly described in aging populations with cerebrovascular disease, extensive lesions also occur in non-vascular diseases. Such lesions are traditionally treated as a separate pathological entity from vascular ones, but recent work has challenged the appropriateness of that framework when probing WMH etiology. Comparing biomarkers associated with WMH across various pathologies may improve our understanding of their etiology. INCLUSION CRITERIA The review will focus on cerebrovascular disease and neurodegenerative disorders and exclude infectious, metabolic, drug-induced, or radiation-induced white matter diseases. Original, peer-reviewed research on the relationship of WMH on magnetic resonance imaging with blood/cerebrospinal fluid biomarkers will be considered for inclusion. Postmortem studies will guide the selection of biomarkers of interest and the interpretation of our findings. Genomic markers will be excluded. METHODS The review will be conducted in accordance with PRISMA and JBI guidelines. English articles of interest published between 2000 and 2020 will be identified in MEDLINE and Embase. Two reviewers will perform abstract and full-text screening, standardized data extraction, and quality assessments of the selected studies. The relationship between each biomarker and WMH burden will be meta-analyzed, if possible, with subgroup or meta-regression analyses to assess differences between diseases. SYSTEMATIC REVIEW REGISTRATION NUMBER PROSPERO CRD42020218298.

It has been suggested by multiple studies (postmortem studies, invasive animal studies, and diffusion tensor imaging in the human brain) that the thalamus is important for communication among cortical regions. Many functional magnetic resonance imaging (fMRI) studies, including noninvasive and whole-brain studies, have reported thalamic co-activation with several cognitive control-related cortical systems. This forms a complex network that may be important for advanced cognitive control-related processes, such as working memory and attention. Nevertheless, how the thalamus communicates with the cognitive control-related network in the intact human brain is an essential question and needs further investigation. To address this question, we conducted a study using dynamic functional connectivity analysis and effective connectivity analysis based on fMRI data from young, healthy adult participants. The results showed that the middle thalamus exhibited both high in- and out-degree regarding the complex network related to cognitive control during both rest and task conditions. Furthermore, intrinsic communication via the middle thalamic regions showed dynamically co-varying patterns, and the thalamic regions showed high flexibility in dynamic community analysis. These results indicated that the mid-thalamic region is an important station for communication between nodes in cognitive control-related networks.

In many neurological disorders, neuroinflammation contributes not only to the neuropathogenic process but also regulates hippocampal neurogenesis, which plays a critical role in cognitive and emotional functions. A major challenge is to understand how inflammation establishes the neurogenic niche microenvironment to affect the behavior of neural stem cells (NSCs) and/or neural progenitor cells (NPCs). The present review discusses recent advances of research that address such a critical question. During the past few years, several human postmortem studies have demonstrated that adult neurogenesis declines significantly during aging and neurological disorders, and that infiltration/activation of T cells and activation of microglia in the neurogenic niche may play a critical role in such decline. Neuroinflammation is believed to play a detrimental role in neurodegenerative and regenerative processes. However, the effect of neuroinflammation on neurogenesis appears to be complex, since it depends not only on the various components of inflammatory responses (immune cells and cytokines) present in the microenvironment of neurogenic niches but also on the physiological and differentiation status of NSCs.

Introduction Synaptic loss is an early pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in the medial temporal and neocortical regions of participants with AD, using in vivo positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A), a promising biomarker of synaptic density. Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in AD however, have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivothe association between fibrillar Aβ deposition and synaptic density in early AD using [11C]PiB and [11C]UCB-J PET. We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI, a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). Methods [11C]UCB-J (for SV2A) and [11C]PiB (Aβ deposition) binding were measured in 14 participants with aMCI due to AD, 24 participants with mild AD dementia, and 19 cognitively normal (CN) participants aged 55-85 years. For [11C]PiB data analysis, parametric images of binding potential (BPND) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, BPNDwas computed using SRTM2 with a shrunken centrum semiovale reference region and converted to DVR with a cerebellum reference region. For the primary analysis of the association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI and dementia, separate univariate regression analyses were performed for each diagnostic group with Pearson r and associated two-tailed P values reported for each model. Fisher z-transformation assessed significant differences in correlation coefficients between the aMCI and dementia groups, with one-tailed P values reported. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Global Aβ deposition was determined for a composite of regions commonly affected by Aβ deposition in AD which included: prefrontal, lateral temporal, posterior cingulate/precuneus, and lateral parietal ROIs. Results The AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in the medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = -0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z= -1.80, P = 0.04; Figure 2).This stronger association was observed to survive partial volume correction (aMCI r= -0.56, P= 0.04; dementia r= -0.01, P= 0.96; Fisher z= -1.67, P= 0.047). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a nominal inverse association in the dementia group between local Aβ deposition and SV2A binding in medial occipital cortex and a more compelling, larger positive correlation between local Aβ accumulation and synaptic density in hippocampus (Table 1). Conclusions To our knowledge, we have conducted the first in vivo study investigating the relationship between Aβ deposition and synaptic alterations in participants with AD. We observed significant inverse associations between measures of global Aβ deposition and hippocampal synaptic density within participants with aMCI but not with dementia. Our findings lend support to a model in which fibrillar Aβ may still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research shouldinvestigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers. Funding P50-AG047270 (CHvD), P30-AG066508 [CHvD], K23-AG057794 (APM), R01-AG052560 (REC, CHV), R01-AG062276 (CHvD), Dana Foundation (MKC), T32-MH019961 (RSO), and Thomas P. Detre Fellowship (RSO).

Background: The human adrenal gland shows a distinct proportion of two histological zones, named the cortex and the medulla, from outer inwards, in its histological appearance with differences in its cellular components and functions. Objective: The present study aims to see the variation in the proportion of the cortex and the medulla of the adrenal glands with age in a Bangladeshi population. Methods: A cross-sectional, descriptive study was done in the Department of Anatomy, Dhaka Medical College, Dhaka, from July 2008 to June 2009, based on collection of 140 postmortem human adrenal glands from 70 unclaimed dead bodies, in the Department of Forensic Medicine, Dhaka Medical College, Dhaka. The samples were divided into four age-groups including A (11-20 years), B (21-30 years), C (31-40 years) & D (41-60 years). Histological slides were prepared by using routine haematoxylin and eosin stain (H & E). Five best prepared slides from each group were examined under light compound microscope with low magnification. The thickness of adrenal cortex and medulla were measured by using ocular and stage micrometer and then converted into percentage volume. Results: The mean volume of the right adrenal cortex were found 83.64±3.71% in group A, 83.90±1.75% in group B, 83.74±5.78% in group C, 84.80±3.82% in group D, while the mean volume of the corresponding medulla were found 18.16±3.23% in group A, 15.70±2.71% in group B, 16.26±3.97% in group C, 16.20±4.04% in group D. The mean volume of the left adrenal cortex were found 84.64±3.49%, 84.90±1.75%, 84.20±3.40%, 85.44±2.66% in group A, B, C and D respectively, while the mean volume of the corresponding medulla were found 17.26±3.84%, 17.00±2.37%, 16.00±3.20% and 14.36±2.33% in group A, B, C and D respectively. The differences among the groups were not statistically significant. Conclusion: No difference was found in the proportion of the cortex and the medulla of adrenal gland in different age-groups. Mediscope Vol. 8, No. 1: January 2021, Page 1-6

Astrocytes are the primary homeostatic cells of the central nervous system, essential for normal neuronal development and function, metabolism and response to injury and inflammation. Here, we review postmortem studies examining changes in astrocytes in subjects diagnosed with the neuropsychiatric disorders schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BPD). We discuss the astrocyte-related changes described in the brain in these disorders and the potential effects of psychotropic medication on these findings. Finally, we describe emerging tools that can be used to study the role of astrocytes in neuropsychiatric illness.

The intracranial arteries play a major role in cerebrovascular disease, but arterial remodeling due to hypertension has not been well described in humans. We aimed to quantify this remodeling for: the basilar artery, the vertebral, internal carotid, middle/anterior (inferior)/posterior cerebral, posterior communicating, and superior cerebellar arteries of the circle of Willis. Ex vivo circle of Willis specimens, selected from individuals with (n=24) and without (n=25) a history of hypertension, were imaged at 7T magnetic resonance imaging using a 3-dimensional gradient-echo sequence. Subsequently, histological analysis was performed. We validated the vessel wall thickness and area measurements from magnetic resonance imaging against histology. Next, we investigated potential differences in vessel wall thickness and area between both groups using both techniques. Finally, using histological analysis, we investigated potential differences in arterial wall stiffness and atherosclerotic plaque severity and load. All analyses were unadjusted. Magnetic resonance imaging and histology showed comparable vessel wall thickness (mean difference: 0.04 mm (limits of agreement:−0.12 to 0.19 mm) and area (0.43 mm 2 [−0.97 to 1.8 mm 2 ]) measurements. We observed no statistically significant differences in vessel wall thickness and area between both groups using either technique. Histological analysis showed early and advanced atherosclerotic plaques in almost all arteries for both groups. The arterial wall stiffness was significantly higher for the internal carotid artery in the hypertensive group. Concluding, we did not observe vessel wall thickening in the circle of Willis arteries in individuals with a history of hypertension using either technique. Using histological analysis, we observed a difference in vessel wall composition for the internal carotid artery.

Microglia, the immune cells of the brain, are important for neurodevelopment and have been hypothesized to play a role in the pathogenesis of schizophrenia (SCZ). Although previous postmortem studies pointed toward presence of microglial activation, this view has been challenged by more recent hypothesis‐driven and hypothesis‐free analyses. The aim of the present study is to further understand the observed microglial changes in SCZ. We first performed a detailed meta‐analysis on studies that analyzed microglial cell density, microglial morphology, and expression of microglial‐specific markers. We then further explored findings from the temporal cortex by performing immunostainings and qPCRs on an additional dataset. A random effect meta‐analysis showed that the density of microglial cells was unaltered in SCZ (ES: 0.144 95% CI: 0.102 to 0.390, p = .250), and clear changes in microglial morphology were also absent. The expression of several microglial specific genes, such as CX3CR1, CSF1R, IRF8, OLR1, and TMEM119 was decreased in SCZ (ES: −0.417 95% CI: −0.417 to −0.546, p, Main Points Microglia density is unaltered in postmortem brain tissue of schizophrenia patients, but several mature microglial markers are downregulated in schizophrenia. This expression pattern is largely opposite from microglial changes in Alzheimer's disease.

Post-mortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we therefore combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (pd = +1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (pAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.

Serotonin-2A (5-HT2A) receptors play an important role in the regulation of many brain functions that are disturbed in patients with such psychiatric diseases as mood disorders and schizophrenia. T...

Background Deep brain stimulation is an established symptomatic surgical therapy for Parkinson disease, essential tremor, and a number of other movement and neuropsychiatric disorders. The well-established foreign body response around implanted electrodes is marked by gliosis, neuroinflammation, and neurodegeneration. However, how this response changes with the application of chronic stimulation is less well-understood. Objective To integrate the most recent evidence from basic science, patient, and postmortem studies on the effect of such an "active" electrode on the parenchyma of the living brain. Methods A thorough and in-part systematic literature review identified 49 papers. Results Increased electrode-tissue impedance is consistently observed in the weeks following electrode implantation, stabilizing at approximately 3 to 6 mo. Lower impedance values are observed around stimulated implanted electrodes when compared with unstimulated electrodes. A temporary reduction in impedance has also been observed in response to stimulation in nonhuman primates. Postmortem studies from patients confirm the presence of a fibrous sheath, astrocytosis, neuronal loss, and neuroinflammation in the immediate vicinity of the electrode. When comparing stimulated and unstimulated electrodes directly, there is some evidence across animal and patient studies of altered neurodegeneration and neuroinflammation around stimulated electrodes. Conclusion Establishing how stimulation influences the electrical and histological properties of the surrounding tissue is critical in understanding how these factors contribute to DBS efficacy, and in controlling symptoms and side effects. Understanding these complex issues will aid in the development of future neuromodulation systems that are optimized for the tissue environment and required stimulation protocols.

Background: Cognitive deficits arising in the course of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients. Objective: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau). Methods: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N = 24), PDD (N = 18), DLB (N = 27), and SCD (N = 28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE). Results: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p = 0.002) and of ZnT3 and Dynamin 1 in DLB (p = 0.001, p = 0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p = 0.011), and with depressive symptoms in SCD (p = 0.041). Conclusion: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development.

We describe an autopsied patient with familial parkinsonism and unclassified four repeat-tau (4R-tau) aggregation. She presented with bradykinesia, truncal dystonia, and mild amnesia at the age of 61 and then exhibited body weight loss (15 kg over 8 months), sleep disturbances, and progressive respiratory failure with CO2 narcosis. She died of respiratory failure at the age of 62, 14 months after disease onset. Her brother also showed parkinsonism at the age of 58 and suddenly died 6 months later. Postmortem examination revealed 4R-tau aggregation, which was characterized by neuronal globose-type tangles or pretangles, bush-like or miscellaneous astrocytic inclusions, and coiled bodies. The temporal tip, the striatum, the substantia nigra, the tegmentum of the midbrain, the medullary reticular formation, and the spinal cord were severely involved with tau aggregation. Argyrophilic grains and ballooned neurons were also found in the medial temporal structures, however, extensions of the 4R-aggregations in the case were clearly broader than those of the argyrophilic grains. Western blot analysis of sarkosyl-insoluble fractions from brain lysates revealed prominent bands of tau at both 33 kDa and 37 kDa. Genetic examinations did not reveal any known pathogenic mutations in MAPT, DCTN-1, PSEN-1, or familial or young-onset parkinsonism-related genes. The clinical manifestations, pathologic findings, and biochemical properties of aggregated tau in our patient cannot be explained by argyrophilic grain disease or other known 4R-tauopathies alone. Our results further extend the clinical and neuropathologic spectra of 4R-tauopathy.

Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large-sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.

AIMS: Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. METHODS: Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. RESULTS: Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P

Major depressive disorder (MDD) is a highly prevalent debilitating psychiatric disease and a serious public health problem worldwide. Brain structural MRI and postmortem studies on patients with depression have revealed changes in the anatomy and functionality in various brain regions, including the amygdala, thalamus, hippocampus, and prefrontal cortex (PFC). The alterations in these brain regions could be a result, in part, of the dysregulation of the neurotrophic factors. Neuregulin1 (NRG1) is one of the neurotrophic factors, and our previous study showed that the NRG1-ErbB4 signaling pathway plays a critical role in epilepsy. In this study, we established a chronic social defeat stress (CSDS) model to investigate the role of the NRG1-ErbB4 signaling pathway in depression-like behaviors. In CSDS mice, we found that the NRG1 protein expression levels were significantly decreased both in the medial prefrontal cortex (mPFC) and hippocampus, while phosphorylated ErbB4 only decreased in the mPFC. In addition, lateral ventricle NRG1 administration significantly rescued depression-like behaviors in the susceptible group. The current study suggests that the NRG1-ErbB4 signaling pathway may exert a protective role in MDD.

Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia’s pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone. Fil: Alvarez, Rodrigo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina Fil: Pafundo, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina Fil: Zold, Camila Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina Fil: Belforte, Juan Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina

Essential tremor (ET) is the most common tremor disorder globally and is characterized by kinetic tremor of the upper limbs, although other clinical features can also occur. Postmortem studies are a particularly important avenue for advancing our understanding of the pathogenesis of ET; however, until recently, the number of such studies has been limited. Several recent postmortem studies have made important contributions to our understanding of the pathological changes that take place in ET. These studies identified abnormalities in the cerebellum, which primarily affected Purkinje cells (PCs), basket cells and climbing fibres, in individuals with ET. We suggest that some of these pathological changes (for example, focal PC axonal swellings, swellings in and regression of the PC dendritic arbor and PC death) are likely to be primary and degenerative. By contrast, other changes, such as an increase in PC recurrent axonal collateral formation and hypertrophy of GABAergic basket cell axonal processes, could be compensatory responses to restore cerebellar GABAergic tone and cerebellar cortical inhibitory efficacy. Such compensatory responses are likely to be insufficient, enabling the disease to progress. Here, we review the results of recent postmortem studies of ET and attempt to place these findings into an anatomical–physiological disease model. In this Review, the authors discuss the results of recent postmortem studies of essential tremor and propose a disease model that involves both primary neurodegenerative changes and compensatory responses.

Postmortem studies on patients with Alzheimer’s disease (AD) have confirmed that the dorsal raphe nucleus (DRN) in the brainstem is the first brain structure affected in the earliest stage of AD. The present study examined the brainstem in the early stage of AD using magnetic resonance (MR) imaging. T1-weighted MR images of the brains of 81 subjects were obtained from the publicly available Open Access Series of Imaging Studies (OASIS) database, including 27 normal control (NC) subjects, 27 patients with very mild AD (AD-VM) and 27 patients with mild AD (AD-M). The brainstem was interactively segmented from the MR images using ITK-SNAP. The present voxel-based morphometry (VBM) study was designed to investigate the brainstem differences between the AD-VM/AD-M groups and the NC group. The results showed bilateral loss in the pons and the left part of the midbrain in the AD-M group compared to the NC group. The AD-M group showed greater loss in the left midbrain than the AD-VM group (PFWEcorrected

Our previous postmortem studies on neonates with neuropathological injury of perinatal hypoxia/ischemia (PHI) showed a dramatic reduction of tyrosine hydroxylase expression (dopamine synthesis enzyme) in substantia nigra (SN) neurons, with reduction of their cellular size. In order to investigate if the above observations represent an early stage of SN degeneration, we immunohistochemically studied the expression of cleaved caspase-3 (CCP3), apoptosis inducing factor (AIF), and DNA fragmentation by using terminal deoxynucleotidyltransferase-mediated dUTP-biotin 3′-end-labeling (TUNEL) technique in the SN of 22 autopsied neonates (corrected age ranging from 34 to 46.5 gestational weeks), in relation to the severity/duration of PHI injury, as estimated by neuropathological criteria. No CCP3-immunoreactive neurons and a limited number of apoptotic TUNEL-positive neurons with pyknotic characteristics were found in the SN. Nuclear AIF staining was revealed only in few SN neurons, indicating the presence of early signs of AIF-mediated degeneration. By contrast, motor neurons of the oculomotor nucleus showed higher cytoplasmic AIF expression and nuclear translocation, possibly attributed to the combined effect of developmental processes and increased oxidative stress induced by antemortem and postmortem factors. Our study indicates the activation of AIF, but not CCP3, in the SN and oculomotor nucleus of the human neonate in the developmentally critical perinatal period.

Accumulating studies have implicated intracellular signaling through muscarinic acetylcholine receptors (mAChRs) in psychiatric illness. In the present study, carbamylcholine chloride (carbachol)-induced Gαi/o and Gαq/11 activation was identified in postmortem human prefrontal cortical membranes. The following two sample cohorts were used: subjects [1], consisting of 40 controls without neuropsychiatric disorders, and subjects [2], consisting of 20 with bipolar disorder (BP), 20 major depressive disorder (MDD), 20 schizophrenia, and 20 controls, strictly sex- and age-matched. Carbachol-stimulated [35S]GTPγS binding to human brain membranes was assessed by the two methods, i.e., conventional method using filtration techniques (Gαi/o activation coupled to M2/M4 mAChRs) applied to subjects [1], and [35S]GTPγS binding/immuno precipitation assay (Gαq/11 activation coupled to M1 mAChR) applied to subjects [1] and [2]. The concentration eliciting the half-maximal effect (EC50), maximum percent increase (%Emax), and slope factor were obtained from concentration-response curve of carbachol-induced Gαi/o and Gαq/11 activation. The pEC50 values of both carbachol-induced Gαi/o and Gαq/11 activations in subjects [1] were significantly correlated, though its implications or underlying molecular processes are unclear. The results of M1 mAChR-mediated Gαq/11 activation in subjects [2] indicated no significant disorder-specific alterations. However, the distribution patterns of the pEC50 values showed unequal variances among the groups. There was a significant inverse correlation between the %Emax values and the pEC50 values in subjects with schizophrenia, but not in those with BP or MDD, or controls. These data support the notion that schizophrenia patients consist of biologically heterogeneous subgroups with respect to M1 mAChR-mediated signaling pathways.

Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n = 74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.

Background Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying. Methods The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide. Results In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003). Conclusions With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism., Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10−8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10−8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10−8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10−9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10−9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.

Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions detected during childhood when delayed language onset and social deficits are observed. Children diagnosed with ASD frequently display sensorimotor deficits associated with the cerebellum, suggesting a dysfunction of synaptic circuits. Astroglia are part of the tripartite synapses and postmortem studies reported an increased expression of the glial fibrillary acidic protein (GFAP) in the cerebellum of ASD patients. Astroglia respond to neuronal activity with calcium transients that propagate to neighboring cells, resulting in a functional response known as a calcium wave. This form of intercellular signaling is implicated in proliferation, migration, and differentiation of neural precursors. Prenatal exposure to valproate (VPA) is a preclinical model of ASD in which premature migration and excess of apoptosis occur in the internal granular layer (IGL) of the cerebellum during the early postnatal period. In this study we tested calcium wave propagation in the IGL of mice prenatally exposed to VPA. Sensorimotor deficits were observed and IGL depolarization evoked a calcium wave with astrocyte recruitment. The calcium wave propagation, initial cell recruitment, and mean amplitude of the calcium transients increased significantly in VPA-exposed mice compared to the control group. Astrocyte recruitment was significantly increased in the VPA model, but the mean amplitude of the calcium transients was unchanged. Western blot and histological studies revealed an increased expression of GFAP, higher astroglial density and augmented morphological complexity. We conclude that the functional signature of the IGL is remarkably augmented in the preclinical model of autism.