Dyshomeostatic modulation of Ca-activated K channels in a human neuronal model of KCNQ2 encephalopathy.

Mutations in , which encodes a pore-forming K channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons.

Homer1 promotes dendritic spine growth through ankyrin-G and its loss reshapes the synaptic proteome.

Homer1 is a synaptic scaffold protein that regulates glutamatergic synapses and spine morphogenesis. HOMER1 knockout (KO) mice show behavioral abnormalities related to psychiatric disorders, and HOMER1 has been associated with psychiatric disorders such as addiction, autism disorder (ASD), schizophrenia (SZ), and depression. However, the mechanisms by which it promotes spine stability and its global function in maintaining the synaptic proteome has not yet been fully investigated.

Autism Genetics: Over 100 Risk Genes and Counting.

Researchers from the Autism Sequencing Consortium (ASC) led by Joseph Buxbaum at the Icahn School of Medicine at Mount Sinai report the largest exome sequencing study in autism spectrum disorder (ASD) to date.

KALRN: A central regulator of synaptic function and synaptopathies.

The synaptic regulator, kalirin, plays a key role in synaptic plasticity and formation of dendritic arbors and spines. Dysregulation of the KALRN gene has been linked to various neurological disorders, including autism spectrum disorder, Alzheimer's disease, schizophrenia, addiction and intellectual disabilities. Both genetic and molecular studies highlight the importance of normal KALRN expression for healthy neurodevelopment and function.

TGF-β-Induced Phosphorylation of Usp9X Stabilizes Ankyrin-G and Regulates Dendritic Spine Development and Maintenance.

Signaling by the cytokine transforming growth factor β (TGF-β) has been implicated in a multitude of biological functions; however, TGF-β signaling, particularly in the CNS, remains largely unexplored. ANK3 variants (encoding ankyrin-G) are associated with bipolar disorder, intellectual disability, and autism spectrum disorder, while mutations in USP9X, which encodes a deubiquitinase, are associated with X-linked intellectual disability and autism in humans. Here, we show that TGF-β signaling promotes Usp9X phosphorylation, which enhances its interaction with ankyrin-G and stabilizes ankyrin-G in spines, leading to spine enlargement.

Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD.

Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance.

CNTNAP2 is targeted to endosomes by the polarity protein PAR3.

A decade of genetic studies has established contactin-associated protein-like 2 (CNTNAP2) as a prominent susceptibility gene associated with multiple neurodevelopmental disorders. The development and characterization of Cntnap2 knockout models in multiple species have bolstered this claim by establishing clear connections with certain endophenotypes. Despite these remarkable in vivo findings, CNTNAP2's molecular functions are relatively unexplored, highlighting the need to identify novel protein partners.

Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia.

Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified as a top candidate MR that may be dysregulated in SCZ. We validated as a MR through enrichment analysis of -binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells.

Exchange protein directly activated by cAMP 2 is required for corticotropin-releasing hormone-mediated spine loss.

Corticotropin-releasing hormone is produced in response to acute and chronic stress. Previous studies have shown that activation of the corticotropin-releasing hormone receptor 1 (CRHR1) by corticotropin-releasing hormone results in the rapid loss of dendritic spines which correlates with cognitive dysfunction associated with stress. Exchange protein directly activated by cAMP (EPAC2), a guanine nucleotide exchange factor for the small GTPase Rap, plays a critical role in regulating dendritic spine morphology and has been linked with CRHR1 signalling.

The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons.

GABAergic interneurons are emerging as prominent substrates in the pathophysiology of multiple neurodevelopmental disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and epilepsy. Interneuron excitatory activity is influenced by 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs), which in turn affects excitatory transmission in the central nervous system. Yet how dysregulation of interneuronal AMPARs distinctly contributes to the molecular underpinning of neurobiological disease is drastically underexplored.

CNTNAP2 stabilizes interneuron dendritic arbors through CASK.

Contactin associated protein-like 2 (CNTNAP2) has emerged as a prominent susceptibility gene implicated in multiple complex neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability (ID), and schizophrenia (SCZ). The presence of seizure comorbidity in many of these cases, as well as inhibitory neuron dysfunction in Cntnap2 knockout (KO) mice, suggests CNTNAP2 may be crucial for proper inhibitory network function. However, underlying cellular mechanisms are unclear.

Dendritic structural plasticity and neuropsychiatric disease.

The structure of neuronal circuits that subserve cognitive functions in the brain is shaped and refined throughout development and into adulthood. Evidence from human and animal studies suggests that the cellular and synaptic substrates of these circuits are atypical in neuropsychiatric disorders, indicating that altered structural plasticity may be an important part of the disease biology. Advances in genetics have redefined our understanding of neuropsychiatric disorders and have revealed a spectrum of risk factors that impact pathways known to influence structural plasticity.

Prenatal stress and genetic risk: How prenatal stress interacts with genetics to alter risk for psychiatric illness.

Risk for neuropsychiatric disorders is complex and includes an individual's internal genetic endowment and their environmental experiences and exposures. Embryonic development captures a particularly complex period, in which genetic and environmental factors can interact to contribute to risk. These environmental factors are incorporated differently into the embryonic brain than postnatal one.

Atypical pupillary light reflex in 2-6-year-old children with autism spectrum disorders.

The purpose of this study was to investigate pupillary light reflex (PLR) in 2-6-years-old children with autism spectrum disorders (ASD). A total of 117 medication-free 2-6-year-old boys participated in this study. Sixty participants were diagnosed with ASD (the "ASD group") and the other 57 were in the control group of typical development (the "TD group").