Biology subjects

Kind, P. C.

Publications and source records attributed to Kind, P. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome

Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism-related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1-/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1-/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment rescues did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS.

neuroscience↗

bioRxiv2025

Hypoplasticity in sensory-driven neocortical circuits of the Fragile X syndrome mouse model

Sensory experience and perceptual learning modify the receptive field properties of cortical pyramidal neurons (PNs), primarily through long-term potentiation (LTP). Repetitive sensory stimulation or rhythmic whisker stimulation (RWS), at behaviourally relevant frequencies (8 Hz), can induce long-term potentiation (LTP) of excitatory synapses in typically developing mice in the somatosensory cortex (S1). Fragile X syndrome (FXS) is a leading single gene inherited form of intellectual disability and altered somatosensory processing is a prevalent feature. The Fragile X mouse model (Fmr1-/y mice) similarly exhibits altered somatosensory processing, including altered neuronal circuit function in S1. To assess if LTP in Layer (L) 2/3 PNs is intact upon changes in S1 circuit function we performed ex vivo whole-cell electrophysiology and in vivo two-photon calcium imaging of layer (L) 2/3 pyramidal neurons (PNs) in the S1 cortex of adult male Fragile X (Fmr1-/y) mice and typically developing (Fmr1+/y) control littermates. We found that plasticity induced by repetitive sensory stimulation was impaired in Fmr1-/y mice ex and in vivo compared to controls. L4-evoked synaptic responses were hyperexcitable in L2/3 PNs, consistent with circuit-level disinhibition. Despite this, baseline intrinsic spiking evoked by current steps remained largely unchanged and whisker-evoked activity appeared diminished in vivo, which may be consistent with findings of shortened axon initial segment (AIS) length. We also observed an increase in adaptation to repetitive stimulation in Fmr1-/y L2/3 PNs compared to controls, which may underlie failure to induce plasticity. These findings suggest that L2/3 PNs of S1 in Fmr1-/y mice are hypoplastic, potentially related to disrupted inhibitory control and rapid adaptation during repetitive sensory stimulation. Altogether, impaired LTP in the sensory cortex suggests that the receptive field properties of cortical PNs are less flexible and dynamic, which may contribute to altered somatosensory processing and reactivity in FXS.

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bioRxiv2025

Absence of short-term axon initial segment plasticity in human, mouse, and rat cortical circuits

Maintaining neuronal output with respect to input in the physiological range relies on the ability of neurons to update their responsiveness to inputs dependent on changing activity levels. Termed homeostatic plasticity, the mechanisms that neurons employ to control their responsiveness are varied, and proposed to include structural changes to a key neuronal structure - the axon initial segment (AIS). As the site of action potential initiation, the AIS has been postulated to rapidly change its length in response to increased or decreased cellular and circuit activity. To date, AIS structural plasticity has only been tested in tissue cultures and rodent models. In our current study, we assess the ability of neurons to alter their AIS length over a variety of timescales in ex vivo rodent and human brain slices, human neurons derived from induced pluripotent stem cells, and in mice dark-reared during early life; using a combination of electrophysiology and immunohistochemistry. We find no evidence for changes to AIS length following depolarisation for up to 3 hours, despite positive controls confirming modulated activity. However, we do find that neuronal physiological properties are altered by changes in activity - but these are largely independent of action potential initiation associated with the AIS. In summary, we find no evidence supporting a role for AIS structural plasticity in mouse, rat, or human cortical neurons.

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bioRxiv2025

Altered GluN2A levels reduce the emergence of seizure-like events in a rat model of GRIN2A haploinsufficiency

GluN2A-containing NMDA receptors, encoded by the GRIN2A gene, are critical components of excitatory synaptic transmission and are essential for proper brain development and function. Dysregulation of NMDA receptor activity is strongly implicated in the pathophysiology of epilepsy. While excessive GluN2A-mediated signalling can lead to hyperexcitability and seizure generation, loss-of-function mutations in GRIN2A, which result in reduced GluN2A expression, have also been identified in patients with various forms of epilepsy, including focal epilepsies and epileptic encephalopathies. This paradox highlights the complexity of NMDA receptor contributions to network excitability and suggests that both gain- and loss-of-function mutations can be pathogenic. However, the mechanisms through which reduced GluN2A expression influences seizure susceptibility remains unclear. In this study, we examined the impact of reduced and absence of GluN2A on seizure-like activity using in vitro model system. Hippocampal slices were prepared from wild-type littermate controls (Grin2a+/+), heterozygous (Grin2a+/-) and homozygous (Grin2a-/-) transgenic rats and subjected to pro-convulsant conditions to elicit epileptiform-like events. Specifically, we employed three well established in vitro epilepsy models: (i) 4-aminopyridine (4-AP), (ii) zero-magnesium with elevated potassium (0Mg{superscript 2}/5K), and (iii) high-potassium (high-K+). Local field potentials were recorded from the CA1 pyramidal layer to quantify interictal and seizure-like activity, by measuring latency to onset, event frequency, and duration. Spectral analyses were also conducted to assess alterations in network dynamics. Our findings reveal that reduced GluN2A expression alters the susceptibility of hippocampal circuits to seizure-like activity in a model-dependent manner. In the 4-AP model, Grin2a-/- slices exhibited a significantly lower frequency of interictal events and a delayed onset of seizure-like activity relative to both wild-type and heterozygous slices. In the 0Mg{superscript 2}/5K model, both Grin2a+/- and Grin2a-/- slices displayed reduced seizure susceptibility compared to wild-type. Finally, in the high-K model, Grin2a-/- slices showed a reduced incidence of seizure-like events compared to wild-type controls when extracellular potassium concentration was increased to 7.5 mM, although this effect was less apparent at higher concentrations (9.5 mM). These results suggest that partial or complete loss of GluN2A-containing NMDA receptors reduces the propensity of hippocampal networks to develop epileptiform activity, potentially by altering intrinsic or synaptic excitability. Our findings provide mechanistic insights into how GRIN2A loss-of-function variants may contribute to epilepsy and highlight the need to consider developmental and circuit-level compensations when interpreting the impact of GluN2A disruption.

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bioRxiv2025

Noradrenergic-dependent restoration of visual discrimination in a mouse model of SYNGAP1-related disorder

Atypical sensory processing in neurodevelopmental disorders contributes to cognitive, social, and behavioural disruptions, yet underlying neurophysiological mechanisms remain unclear. Using a mouse model of SYNGAP1 haploinsufficiency (HET), a common monogenic cause of intellectual disability and autism, we investigated visual processing deficits. Syngap HET mice exhibited impaired behavioural visual discriminability, associated with reduced coding precision for visual stimuli in the primary visual cortex (V1). Notably, intrinsic properties of V1 neurons and visual responses under anaesthesia were unaltered, suggesting behavioural state-dependent disruptions in awake Syngap HET mice. Supporting this, both mice and individuals with SYNGAP1 haploinsufficiency exhibited larger pupil size during visual stimulation, implicating neuromodulatory dysfunction. Targeting noradrenergic tone systemically with an 2-adrenergic receptor agonist restored V1 coding precision in Syngap HET mice. Our findings reveal neuromodulatory dysregulation as a novel mechanism underlying sensory disruptions in SYNGAP1-related disorder, highlighting potential therapeutic targets for addressing sensory impairments in neurodevelopmental disorders.

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bioRxiv2024

Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorders.

The key pathological mechanisms underlying autism spectrum disorders (ASDs) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders, however it is unclear whether this dysfunction drives ASDs or is an adaptation to the altered brain microenvironment. To determine this, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in a series of preclinical models of monogenic ASDs. These models were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. However, all models displayed a common trait of hyperexcitability. We determined that SV fusion events and SV cargo trafficking were unaffected in all models investigated. However, a key convergent phenotype was revealed, a depression in activity-dependent bulk endocytosis (ADBE). This suggests that the depression in ADBE is a homeostatic mechanism to correct hyperexcitability in the ASD brain.

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bioRxiv2024

Typical development of synaptic and neuronal properties can proceed without microglia

Brain-resident macrophages, microglia, have been proposed to play an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that a variety of neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse which lacks microglia (Csf1r{Delta}FIRE/{Delta}FIRE) we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated. Seizure susceptibility and hippocampal-prefrontal cortex coherence in awake behaving animals, processes disrupted in mice deficient in microglia-enriched genes, are also normal. Similarly, eye-specific segregation of inputs into the lateral geniculate nucleus proceeds normally in the absence of microglia. Single cell/nucleus transcriptomic analyses of neurons and astrocytes did not uncover any substantial perturbation due to microglial absence. Thus, the brain possesses remarkable adaptability to execute developmental synaptic refinement, maturation and connectivity in the absence of microglia.

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bioRxiv2024

The Fragile X Messenger Ribonucleoprotein 1 regulates the morphology and maturation of human and rat oligodendrocytes

The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to Fragile X Syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendro-cytes, is largely unknown. FXS individuals are characterised by white matter changes which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell - derived oligodendrocytes and an Fmr1 knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro which persist in the presence of FMRP expressing axons in chimeric engraftment models. Our findings point to species-conserved, cell-autonomous defects during oligodendrocyte maturation in FXS.

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bioRxiv2024

Human induced pluripotent stem cell-derived microglia contribute to thepathophysiology of Fragile X syndrome via increased RAC1 signaling

Fragile X syndrome (FXS) is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism and epilepsy. Emerging evidence suggests a role for immune dysfunction in autism. Using induced pluripotent stem cell (iPSC)-derived microglial cells from FXS patients (mFXS-MG) and FMR1-deficient microglia from FMR1-knock out human embryonic stem cells (FMR1 KO-MG), we show that loss-of-function of Fragile X Messenger Ribonucleoprotein (FMRP) leads to cell autonomous phagocytic deficits and a proinflammatory state in microglia when compared to gene-corrected controls. Moreover, increased RAC1 signaling in mFXS-MG and FMR1 KO-MG results in increased actin polymerization and enhanced activation of NF-{kappa}B signaling. Exposure of control iPSC-derived cortical neuron cultures to conditioned medium from proinflammatory mFXS-MG results in hyperexcitability. Importantly, pharmacological inhibition of RAC1 signaling in mFXS-MG attenuates their proinflammatory profile and corrects the neuronal hyperexcitability caused by the conditioned medium. Our results suggest that microglia impair neuronal function in FXS, which can be prevented by targeting of RAC1 signaling. Significance statementFXS is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy and has been associated with immune dysfunction. We therefore generated brain macrophages (microglia) from patient-derived induced pluripotent stem cells (mFXS-MG) and an embryonic stem cell line deficient in the Fragile X messenger ribonucleoprotein 1 (FMR1 KO-MG). We find enhanced activation of RAC1 signaling resulting in phagocytic deficits and immune activation of mFXS-MG and FMR1 KO-MG. Exposure of control iPSC-derived cortical neurons to conditioned medium from proinflammatory mFXS-MG results in neuronal hyperexcitability, which can be prevented by pharmacological RAC1 inhibition in mFXS-MG. We conclude that RAC1 signaling in microglia could be a potential therapeutic target in FXS.

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bioRxiv2024

Absence seizures and sleep abnormalities in a rat model of GRIN2B neurodevelopmental disorder

Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability. GRIN2B encodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novel Grin2b heterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion (Grin2b+/-) had a higher incidence of spontaneous spike and wave discharges, the electrographic correlate of absence seizures, than wild-type rats (Grin2b+/+). Spike and wave discharges were longer in duration and displayed higher overall spectral power in Grin2b+/- when compared to those in Grin2b+/+ animals. Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep in Grin2b+/-. The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options for GRIN2B related epilepsy. Our data shows the new rat Grin2b haploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies for GRIN2B neurodevelopmental disorders.

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bioRxiv2022

Enhanced hippocampal LTP but typical NMDA receptor and AMPA receptor function in a novel rat model of CDKL5 deficiency disorder

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a novel Cdkl5 KO rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5 KO rats. We tested this hypothesis using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. We show that NMDA receptor function and subunit expression are unaltered throughout development, and Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 KO rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability in Cdkl5 KO rats and supported by typical expression of pre-synaptic proteins in synaptosome preparations. Together these data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits might contribute to the altered plasticity.

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bioRxiv2022

Excess ribosomal protein production unbalances translation in Fragile X Syndrome

Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5-induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y). Surprisingly, our results identify a robust translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1-/y neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.

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bioRxiv2022

CDKL5 deficiency slows synaptic vesicle endocytosis

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe early-onset epileptic encephalopathy resulting mainly from de novo mutations in the X-linked CDKL5 gene. To determine whether loss of presynaptic CDKL5 function contributes to CDD, we examined synaptic vesicle (SV) recycling in primary hippocampal neurons generated from a Cdkl5 knockout rat model. Using a genetically-encoded reporter, we revealed that CDKL5 is selectively required for efficient SV endocytosis. We showed that CDKL5 kinase activity is both necessary and sufficient for optimal SV endocytosis, since kinase-inactive mutations failed to correct endocytosis in Cdkl5 knockout neurons, whereas the isolated CDKL5 kinase domain fully restored SV endocytosis kinetics. Finally, we demonstrated that CDKL5-mediated phosphorylation of amphiphysin 1, a putative presynaptic target, is not required for CDKL5-dependent control of SV endocytosis. Overall, our findings reveal a key presynaptic role for CDKL5 kinase activity and enhance our insight into how its dysfunction may culminate in CDD.

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bioRxiv2022

Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase activating protein (GAP) domains have been deleted (Syngap+/{Delta}-GAP) we analysed the duration and occurrence of wake, non rapid eye movement (NREM) and rapid eye movement (REM) brain states during 6 hour multi-electrode EEG recordings. We find that although Syngap+/{Delta}-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and NREM bouts are reduced and there is an increase in the average duration of both wake and NREM epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during NREM is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/{Delta}-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high connectivity instances between short-distance electrode pairs. Finally, by comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. These data suggest that Syngap+/{Delta}-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP haploinsufficiency in humans.

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bioRxiv2021

Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and Autism Spectrum Disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1-/y), and recorded from the CA1 region of the hippocampus while animals habituated in a novel environment for two consecutive days. On the first day of exploration, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1-/y rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1-/y rats. These findings were consistent with increased excitability of Fmr1-/y CA1 neurons in ex-vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were discoordinated with respect to hippocampal oscillatory activity in Fmr1-/y rats. These findings suggest a network-level origin of cognitive deficits in FXS.

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bioRxiv2021

Identifying developing interneurons as a potential target for multiple genetic autism risk factors in human and rodent forebrain.

Autism spectrum condition or autism is associated with numerous monogenic and polygenic genetic risk factors including the polygenic 16p11.2 microdeletion. A central question is what neural cells are affected. To systematically investigate we analysed single cell transcriptomes from gestational week (GW) 8-26 human foetal prefrontal cortex and identified a subset of interneurons (INs) first appearing at GW23 with enriched expression of a disproportionately large fraction of risk factor transcripts. This suggests the hypothesis that these INs are disproportionately vulnerable to mutations causing autism. We investigated this in a rat model of the 16p11.2 microdeletion. We found no change in the numbers or position of either excitatory or inhibitory neurons in the somatosensory cortex or CA1 of 16p11.2+/- rats but found that CA1 Sst INs were hyperexcitable with an enlarged axon initial segment, which was not the case for CA1 pyramidal cells. This study prompts deeper investigation of IN development as a convergent target for autism genetic risk factors.

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bioRxiv2020

Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

Pathogenic variants in SYNGAP1 are one of the most common genetic causes of nonsyndromic intellectual disability (ID) and are considered a risk for autism spectrum disorder (ASD). SYNGAP1 encodes a synaptic GTPase activating protein that modulates the intrinsic GTPase activity of several small G-proteins and is implicated in regulating the composition of the postsynaptic density. By targeting the deletion of exons encoding the calcium/lipid binding (C2) and GTPase activating protein (GAP) domains, we generated a novel rat model to study SYNGAP related pathophysiology. We find that rats heterozygous for the C2/GAP domain deletion (Syngap+/{Delta}-GAP) exhibit reduced exploration and fear extinction, altered social behaviour, and spontaneous seizures, while homozygous mutants die within days after birth. This new rat model reveals that the enzymatic domains of SYNGAP are essential for normal brain function and provide an important new model system in the study of both ID/ASD and epilepsy.

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bioRxiv2020

Demyelination induces selective vulnerability of inhibitory networks in multiple sclerosis

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination proved that this selective neurodegeneration is secondary to demyelination providing the first temporal evidence of demyelination-induced neurodegeneration and a new preclinical model for the study of neuroprotective treatments.

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