Progressive Excitability Changes in the Medial Entorhinal Cortex in the 3xTg Mouse Model of Alzheimer's Disease Pathology.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, before the onset of memory impairments, we found early hyperexcitability in intrinsic properties of MECII stellate and pyramidal cells, but this was balanced by a relative reduction in synaptic excitation (E) compared with inhibition (I; E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable, and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this postsymptomatic time point, which may contribute to the emergence of memory deficits in AD.SIGNIFICANCE STATEMENT AD causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the MEC have altered excitability. Before the onset of memory impairments, neurons in layer 2 of MEC had increased intrinsic excitability, but this was balanced by reduced inputs onto the cell. However, after the onset of memory impairments, stellate cells in MEC became further hyperexcitable, with increased excitability exacerbated by increased synaptic inputs. Thus, it appears that MEC stellate cells are uniquely disrupted during the progression of memory deficits and may contribute to cognitive deficits in AD.

Memory impairment in Amyloidß-status Alzheimer's disease is associated with a reduction in CA1 and dentate gyrus volume: In vivo MRI at 7T.

INTRODUCTION: In Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI). METHODS: We used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidß-status AD and 18 age-matched controls, with respective age ranges of 60 (42-76) and 62 (52-79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study. RESULTS: A significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implied that hippocampal volume loss was not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. The volume of the Dentate Gyrus (DG) showed a significant association with the Memory and Executive domain scores in AD patients as assessed by the UDSNB3.0.. The data also suggested a non-significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. In a reassessment focusing on hippocampal subfields and MoCA memory subdomains in AD, associations were observed between the DG and Cued, Uncued, and Recognition Memory subscores, whereas CA1 and Tail showed associations only with Cued memory. DISCUSSION: This study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy. CLINICALTRIALS: GOV: ID NCT04992975 (Clinicaltrial.gov 2023).

Hippocampal lesions impair non-navigational spatial memory in macaques.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks-which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.

Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.

Organophosphates (OPs) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus (SE), brain injury, or death. There are persistent long-term neurologic and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids, valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP) and were treated with VX or LX in addition to midazolam at 40 minutes postexposure. The extent of neurodegeneration, along with various behavioral and memory deficits, were assessed at 3 months postexposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, and reduced neurodegeneration and cellular neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurologic dysfunction and neurodegeneration associated with OP exposure. SIGNIFICANCE STATEMENT: Survivors of nerve agents and organophosphate (OP) exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish valaxanolone and lysaxanolone as potent and efficacious neuroprotectants suitable for injectable dosing.

Anesthetics fragment hippocampal network activity, alter spine dynamics, and affect memory consolidation.

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging, and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all 3 anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

Associations among body mass index, working memory performance, gray matter volume, and brain activation in healthy children.

To investigate the neural mechanisms underlying the association between poorer working memory performance and higher body mass index (BMI) in children. We employed structural-(sMRI) and functional magnetic resonance imaging (fMRI) with a 2-back working memory task to examine brain abnormalities and their associations with BMI and working memory performance in 232 children with overweight/obesity (OW/OB) and 244 normal weight children (NW) from the Adolescent Brain Cognitive Development dataset. OW/OB had lower working memory accuracy, which was associated with higher BMI. They showed smaller gray matter (GM) volumes in the left superior frontal gyrus (SFG_L), dorsal anterior cingulate cortex, medial orbital frontal cortex, and medial superior frontal gyrus, which were associated with lower working memory accuracy. During the working memory task, OW/OB relative to NW showed weaker activation in the left superior temporal pole, amygdala, insula, and bilateral caudate. In addition, caudate activation mediated the relationship between higher BMI and lower working memory accuracy. Higher BMI is associated with smaller GM volumes and weaker brain activation in regions involved with working memory. Task-related caudate dysfunction may account for lower working memory accuracy in children with higher BMI.

A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment.

Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.

Reevaluating the role of the hippocampus in memory: A meta-analysis of neurotoxic lesion studies in nonhuman primates.

The hippocampus and perirhinal cortex are both broadly implicated in memory; nevertheless, their relative contributions to visual item recognition and location memory remain disputed. Neuropsychological studies in nonhuman primates that examine memory function after selective damage to medial temporal lobe structures report various levels of memory impairment-ranging from minor deficits to profound amnesia. The discrepancies in published findings have complicated efforts to determine the exact magnitude of visual item recognition and location memory impairments following damage to the hippocampus and/or perirhinal cortex. To provide the most accurate estimate to date of the overall effect size, we use meta-analytic techniques on data aggregated from 26 publications that assessed visual item recognition and/or location memory in nonhuman primates with and without selective neurotoxic lesions of the hippocampus or perirhinal cortex. We estimated the overall effect size, evaluated the relation between lesion extent and effect size, and investigated factors that may account for between-study variation. Grouping studies by lesion target and testing method, separate meta-analyses were conducted. One meta-analysis indicated that impairments on tests of visual item recognition were larger after lesions of perirhinal cortex than after lesions of the hippocampus. A separate meta-analysis showed that performance on tests of location memory was severely impaired by lesions of the hippocampus. For the most part, meta-regressions indicated that greater impairment corresponds with greater lesion extent; paradoxically, however, more extensive hippocampal lesions predicted smaller impairments on tests of visual item recognition. We conclude the perirhinal cortex makes a larger contribution than the hippocampus to visual item recognition, and the hippocampus predominately contributes to spatial navigation.

A novel geometry-based analysis of hippocampal morphometry in mesial temporal lobe epilepsy.

Hippocampal volumetry is an essential tool in researching and diagnosing mesial temporal lobe epilepsy (mTLE). However, it has a limited ability to detect subtle alterations in hippocampal morphometry. Here, we establish and apply a novel geometry-based tool that enables point-wise morphometric analysis based on an intrinsic coordinate system of the hippocampus. We hypothesized that this point-wise analysis uncovers structural alterations not measurable by volumetry, but associated with histological underpinnings and the neuropsychological profile of mTLE. We conducted a retrospective study in 204 individuals with mTLE and 57 age- and gender-matched healthy subjects. FreeSurfer-based segmentations of hippocampal subfields in 3T-MRI were subjected to a geometry-based analysis that resulted in a coordinate system of the hippocampal mid-surface and allowed for point-wise measurements of hippocampal thickness and other features. Using point-wise analysis, we found significantly lower thickness and higher FLAIR signal intensity in the entire affected hippocampus of individuals with hippocampal sclerosis (HS-mTLE). In the contralateral hippocampus of HS-mTLE and the affected hippocampus of MRI-negative mTLE, we observed significantly lower thickness in the presubiculum. Impaired verbal memory was associated with lower thickness in the left presubiculum. In HS-mTLE histological subtype 3, we observed higher curvature than in subtypes 1 and 2 (all p < .05). These findings could not be observed using conventional volumetry (Bonferroni-corrected p < .05). We show that point-wise measures of hippocampal morphometry can uncover structural alterations not measurable by volumetry while also reflecting histological underpinnings and verbal memory. This substantiates the prospect of their clinical application.

Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.

Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers - in cognitively unimpaired older adults.

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-ß (Aß-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aß-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

Postoperative seizure and memory outcome of temporal lobe epilepsy with hippocampal sclerosis: A systematic review.

We conducted a systematic review and meta-analysis to evaluate postoperative seizure and memory outcomes of temporal lobe epilepsy with different hippocampal sclerosis (HS) subtypes classified by International League Against Epilepsy (ILAE) Consensus Guidelines in 2013. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-Analysis of Observational Studies in Epidemiology) guidelines, we searched PubMed, Embase, Web of Science, and Cochrane Library from January 1, 2013 to August 6, 2023. Observational studies reporting seizure and memory outcomes among different HS subtypes were included. We used the Newcastle-Ottawa scale to assess the risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to grade the quality of evidence. Seizure freedom and improved outcome (Engel 1 or ILAE class 1-2) ≥1 year after surgery were defined as the primary and secondary seizure outcome. A random-effects meta-analysis by DerSimonian and Laird method was performed to obtain pooled risk ratio (RRs) with 95% confidence interval (CIs). The memory impairment was narratively reviewed because of various evaluation tools. Fifteen cohort studies with 2485 patients were eligible for the meta-analysis of seizure outcome. Six cohorts with detailed information on postoperative memory outcome were included. The pooled RRs of seizure freedom, with moderate to substantial heterogeneity, were .98 (95% CI = .84-1.15) between HS type 2 and type 1, 1.11 (95% CI = .82-1.52) between type 3 and type 1, and .80 (95% CI = .62-1.03) between the no-HS and HS groups. No significant difference of improved outcome was found between different subtypes (p > .05). The quality of evidence was deemed to be low to very low according to GRADE. The long-term seizure outcome (≥5 years after surgery) and memory impairment remained controversial.

Meprin ß knockout reduces brain Aß levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.

ß-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described ß-secretase to generate Aß peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative Aß peptides generation is the metalloproteinase meprin ß, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin ß expression in AD brain. Here, we report the generation of the transgenic APP/lon mouse model of AD lacking the functional Mep1b gene (APP/lon × Mep1b-/-). We examined levels of canonical and truncated Aß species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse × Mep1b-/-. Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. Aß1-40 and 1-42 levels are reduced in APP/lon mice when meprin ß is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated Aß2-x peptide deposition is decreased in APP/lon × Mep1b-/- mice. Importantly, loss of meprin ß improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin ß within the amyloidogenic pathway and Aß production in vivo.

Effects of prenatal exposure to maternal diabetes mellitus on deep grey matter structures and attention deficit hyperactivity disorder symptoms in children.

AIM: The neuronal mechanism linking the association between maternal diabetes mellitus (DM) and risk of attention deficit hyperactivity disorder (ADHD) symptoms and working memory deficits in children was investigated. METHODS: A total of 6291 children (52% boys) born beyond 28 weeks of gestation were included and underwent brain magnetic resonance imaging scans at 9-10 years. Subcortical brain volumes were estimated from the T1-weighted images. ADHD symptoms were assessed using factorial analysis of the Child Behaviour Checklist completed by parents/caregivers. Working memory performance was assessed with the NIH Toolbox. RESULTS: Compared to unexposed children, those exposed to DM (n = 422) had smaller (ß = -0.15, p = 0.001) volumes of pooled deep grey matter (GM). Regional analysis revealed smaller volumes of the caudate nucleus, putamen, thalamus and cerebellum but not of hippocampus. They also had altered cortico-striatal white matter projection tracts. DM was not associated with working memory deficits or inattention, but with increased hyperactivity/impulsivity and Sluggish Cognitive Tempo symptoms in boys. This hyperactivity/impulsivity symptom in boys was partially mediated by smaller deep GM volume. CONCLUSION: Exposure to DM during pregnancy leads to altered deep GM development during late childhood in their offspring. This contributed to an increased risk of hyperactivity/impulsivity symptoms in boys.

Volume atrophy in medial temporal cortex and verbal memory scores in American Indians: Data from the Strong Heart Study.

INTRODUCTION: Distinguishing Alzheimer's disease (AD) patient subgroups may optimize positive clinical outcomes. Cortical atrophy is correlated with memory deficits, but these associations are understudied in American Indians. METHODS: We collected imaging and cognition data in the Strong Heart Study (SHS), a cohort of 11 tribes across three regions. We processed 1.5T MRI using FreeSurfer and iterative principal component analysis. Linear mixed models estimated volumetric associations with diabetes. RESULTS: Over mean 7 years follow-up (N = 818 age 65-89 years), overall volume loss was 0.5% per year. Significant losses associated with diabetes were especially strong in the right hemisphere. Annualized hippocampal, parahippocampal, entorhinal atrophy were worse for men, older age, diabetes, hypertension, stroke; and associated with both encoding and retrieval memory losses. DISCUSSION: Our findings suggest that diabetes is an important risk factor in American Indians for cortical atrophy and memory loss. Future research should examine opportunities for primary prevention in this underserved population.

Delayed TBI-Induced Neuronal Death in the Ipsilateral Hippocampus and Behavioral Deficits in Rats: Influence of Corticosterone-Dependent Survivorship Bias?

Acute and chronic corticosterone (CS) elevations after traumatic brain injury (TBI) may be involved in distant hippocampal damage and the development of late posttraumatic behavioral pathology. CS-dependent behavioral and morphological changes were studied 3 months after TBI induced by lateral fluid percussion in 51 male Sprague-Dawley rats. CS was measured in the background 3 and 7 days and 1, 2 and 3 months after TBI. Tests including open field, elevated plus maze, object location, new object recognition tests (NORT) and Barnes maze with reversal learning were used to assess behavioral changes in acute and late TBI periods. The elevation of CS on day 3 after TBI was accompanied by early CS-dependent objective memory impairments detected in NORT. Blood CS levels > 860 nmol/L predicted delayed mortality with an accuracy of 0.947. Ipsilateral neuronal loss in the hippocampal dentate gyrus, microgliosis in the contralateral dentate gyrus and bilateral thinning of hippocampal cell layers as well as delayed spatial memory deficits in the Barnes maze were revealed 3 months after TBI. Because only animals with moderate but not severe posttraumatic CS elevation survived, we suggest that moderate late posttraumatic morphological and behavioral deficits may be at least partially masked by CS-dependent survivorship bias.

Modality-Specific Impairment of Hippocampal CA1 Neurons of Alzheimer's Disease Model Mice.

Impairment of episodic memory, a class of memory for spatiotemporal context of an event, is an early symptom of Alzheimer's disease. Both spatial and temporal information are encoded and represented in the hippocampal neurons, but how these representations are impaired under amyloid ß (Aß) pathology remains elusive. We performed chronic imaging of the hippocampus in awake male amyloid precursor protein (App) knock-in mice behaving in a virtual reality environment to simultaneously monitor spatiotemporal representations and the progression of Aß depositions. We found that temporal representation is preserved, whereas spatial representation is significantly impaired in the App knock-in mice. This is because of the overall reduction of active place cells, but not time cells, and compensatory hyperactivation of remaining place cells near Aß aggregates. These results indicate the differential impact of Aß aggregates on two major modalities of episodic memory, suggesting different mechanisms for forming and maintaining these two representations in the hippocampus.

Fornix volumetric increase and microglia morphology contribute to spatial and recognition-like memory decline in ageing male mice.

Ageing displays a low-grade pro-inflammatory profile in blood and the brain. Accumulation of pro-inflammatory cytokines, microglia activation and volumetric changes in the brain correlate with cognitive decline in ageing models. However, the interplay between them is not totally understood. Here, we aimed to globally identify an age-dependent pro-inflammatory profile and microglia morphological plasticity that favors major volume changes in the brain associated with cognitive decline. Cluster analysis of behavioral data obtained from 2-,12- and 20-month-old male C57BL/6 mice revealed age-dependent cognitive decline after the Y-maze, Barnes maze, object recognition (NORT) and object location tests (OLT). Global magnetic resonance imageing (MRI) analysis by deformation-based morphometry (DBM) in the brain identified a volume increase in the fornix and a decrease in the left medial entorhinal cortex (MEntC) during ageing. Notably, the fornix shows an increase in the accumulation of pro-inflammatory cytokines, whereas the left MEntC displays a decrease. Morphological assessment of microglia also confirms an active and dystrophic phenotype in the fornix and a surveillance phenotype in the left MEntC. Finally, biological modeling revealed that age-related volume increase in the fornix was associated with dystrophic microglia and cognitive impairment, as evidenced by failure on tasks examining memory of object location and novelty. Our results propose that the morphological plasticity of microglia might contribute to volumetric changes in brain regions associated with cognitive decline during physiological ageing.

Combination of whole exome sequencing and animal modeling identifies TMPRSS9 as a candidate gene for autism spectrum disorder.

Autism spectrum disorders are associated with some degree of developmental regression in up to 30% of all cases. Rarely, however, is the regression so extreme that a developmentally advanced young child would lose almost all ability to communicate and interact with her surroundings. We applied trio whole exome sequencing to a young woman who experienced extreme developmental regression starting at 2.5 years of age and identified compound heterozygous nonsense mutations in TMPRSS9, which encodes for polyserase-1, a transmembrane serine protease of poorly understood physiological function. Using semiquantitative polymerase chain reaction, we showed that Tmprss9 is expressed in various mouse tissues, including the brain. To study the consequences of TMPRSS9 loss of function on the mammalian brain, we generated a knockout mouse model. Through a battery of behavioral assays, we found that Tmprss9-/- mice showed decreased social interest and social recognition. We observed a borderline recognition memory deficit by novel object recognition in aged Tmprss9-/- female mice, but not in aged Tmprss9-/- male mice or younger adult Tmprss9-/- mice in both sexes. This study provides evidence to suggest that loss of function variants in TMPRSS9 are related to an autism spectrum disorder. However, the identification of more individuals with similar phenotypes and TMPRSS9 loss of function variants is required to establish a robust gene-disease relationship.

Nr2f1 heterozygous knockout mice recapitulate neurological phenotypes of Bosch-Boonstra-Schaaf optic atrophy syndrome and show impaired hippocampal synaptic plasticity.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein's role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model and found that this model recapitulates some of the neurological phenotypes of BBSOAS, including altered learning/memory, hearing defects, neonatal hypotonia and decreased hippocampal volume. The mice showed altered fear memory, and further electrophysiological investigation in hippocampal slices revealed significantly reduced long-term potentiation and long-term depression. These results suggest that a deficit or alteration in hippocampal synaptic plasticity may contribute to the intellectual disability frequently seen in BBSOAS. RNA-sequencing (RNA-Seq) analysis revealed significant differential gene expression in the adult Nr2f1+/- hippocampus, including the up-regulation of multiple matrix metalloproteases, which are known to be critical for the development and the plasticity of the nervous system. Taken together, our studies highlight the important role of Nr2f1 in neurodevelopment. The discovery of impaired hippocampal synaptic plasticity in the heterozygous mouse model sheds light on the pathophysiology of altered memory and cognitive function in BBSOAS.