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Development of New IL-1R Antagonists with Improved Anti-inflammatory Efficacy Open
Background: Anakinra, a recombinant human interleukin-1 receptor antagonist (hIL-1Ra), is a widely used anti-inflammatory biologic for conditions like rheumatoid arthritis and gout. However, its limited potency and dose-dependent side effe…
Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms Open
Vertebrate neural circuit properties are shaped by synaptic cell adhesion molecules (CAMs). CAMs often have multiple paralogs but the possible redundancy of such paralogs remains underexplored. Using circuit-specific conditional knockout (…
Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice Open
Background: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, resulting in a polyglutamine-expanded huntingtin (HTT) protein that forms toxic aggregates. Although heat-sho…
View article: CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses
CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses Open
Presynaptic active zones (AZs) perform essential functions in orchestrating speedy and accurate neurotransmission. Despite extensive studies on their molecular constituents, it remains unclear how transsynaptic signals are organized at AZs…
View article: Autism-associated ARHGEF9 variants impair GABAergic synapses and ultrasonic communication by reducing gephyrin phosphorylation
Autism-associated ARHGEF9 variants impair GABAergic synapses and ultrasonic communication by reducing gephyrin phosphorylation Open
Missense and truncating variants of the X-chromosome-linked ARHGEF9 gene encoding collybistin (Cb) cause intellectual disability and epilepsy. Here we report novel rare variants in ARHGEF9 identified via exome sequencing in male individual…
View article: <i>MDGA2</i> homozygous loss-of-function variants cause developmental and epileptic encephalopathy
<i>MDGA2</i> homozygous loss-of-function variants cause developmental and epileptic encephalopathy Open
Summary MDGA2 encodes a membrane-associated protein that is critical for regulating glutamatergic synapse development, modulating neuroligins (Nlgns), and maintaining the balance between excitatory and inhibitory synapses. Although MDGA2 h…
View article: Autism-associated MDGA1 missense mutations impair distinct facets of central nervous system development
Autism-associated MDGA1 missense mutations impair distinct facets of central nervous system development Open
MDGA1 reportedly suppresses GABAergic synaptic inhibition, but it is unclear whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe two patients with autism spectrum disorders (ASDs) each carrying pairs of…
Bazedoxifene rescues sexually dimorphic autistic-like abnormalities in mice carrying a biallelic <i>MDGA1</i> mutation Open
In the accompanying study, we describe two pairs of MDGA1 missense mutations (Val116Met/Ala688Val and Tyr635Cys/Glu756Gln) from two patients with autism spectrum disorders (ASDs) and how these mutations exert distinct abnormalities in biol…
View article: The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions
The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions Open
Neuroinflammation is a well-established risk factor for various neurological disorders and cognitive decline. However, the precise molecular mechanisms linking inflammation with neuropsychiatric symptoms remain unclear. Here, using NLRP3 (…
Light-activated tetanus neurotoxin for conditional proteolysis and inducible synaptic inhibition <i>in vivo</i> Open
The light chain of tetanus neurotoxin (TeNT) is a 52 kD metalloprotease that potently inhibits synaptic transmission by cleaving the endogenous vesicle fusion protein VAMP2. To mitigate the toxicity of TeNT and harness it as a conditional …
View article: MDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms
MDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms Open
MDGA (MAM domain containing glycosylphosphatidylinositol anchor) family proteins were previously identified as synaptic suppressive factors. However, various genetic manipulations have yielded often irreconcilable results, precluding preci…
View article: Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons
Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons Open
LAR-RPTPs are evolutionarily conserved presynaptic cell-adhesion molecules that orchestrate multifarious synaptic adhesion pathways. Extensive alternative splicing of LAR-RPTP mRNAs may produce innumerable LAR-RPTP isoforms that act as reg…
Differential Regional Vulnerability of the Brain to Mild Neuroinflammation Induced by Systemic LPS Treatment in Mice Open
Our results suggest that mild neuroinflammation induces regionally different microglia activation, producing pro-inflammatory cytokines. Our observations provide insight into induction of possible region-specific neuroinflammation-associat…
MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus Open
Balanced synaptic inhibition, controlled by multiple synaptic adhesion proteins, is critical for proper brain function. MDGA1 (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu [MAM] domain-containing glycosylphosphatidylin…
LRRTM3 regulates activity-dependent synchronization of synapse properties in topographically connected hippocampal neural circuits Open
Significance The present study utilized imaging, electrophysiology, and three-dimensional high-resolution electron microscopy analyses to address the neural circuit role of LRRTM3 in vivo, using both conventional and conditional Lrrtm3 -KO…
Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior Open
Activity-dependent GABAergic synapse plasticity is important for normal brain functions, but the underlying molecular mechanisms remain incompletely understood. Here, we show that Npas4 (neuronal PAS-domain protein 4) transcriptionally reg…
Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies Open
Gephyrin is critical for the structure, function, and plasticity of inhibitory synapses. Gephyrin mutations have been linked to various neurological disorders; however, systematic analyses of the functional consequences of these mutations …
LAR-RPTPs Directly Interact with Neurexins to Coordinate Bidirectional Assembly of Molecular Machineries Open
Neurexins (Nrxns) and LAR-RPTPs (leukocyte common antigen-related protein tyrosine phosphatases) are presynaptic adhesion proteins responsible for organizing presynaptic machineries through interactions with nonoverlapping extracellular li…
Receptor protein tyrosine phosphatase delta is not essential for synapse maintenance or transmission at hippocampal synapses Open
Members of the leukocyte common antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family, comprising PTPσ, PTPδ and LAR, are key hubs for presynaptic assembly and differentiation in vertebrate neurons. However, roles of indi…