Biology subjects

Dargaei, Z.

Publications and source records attributed to Dargaei, Z..

3 recordsLinked to original sources

bioRxiv2025

The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis

Voltage-gated sodium channels regulate neuronal excitability and synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD) and a broad spectrum of epilepsy phenotypes, including early-onset developmental and epileptic encephalopathies. The expression pattern of SCN2A begins during prenatal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated Sonic hedgehog signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to Nav1.2-dependent sodium channel dysfunction and reduced action potential generation, leading to abnormal neuronal network activity. Our results identify a mechanism for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precede postnatal neural circuit dysfunction in SCN2A-associated disorders.

neuroscience↗

bioRxiv2020

Astrocytic Neurexin-1 Orchestrates Functional Synapse Assembly

At tripartite synapses, astrocytes enmesh synaptic contacts, but how astrocytes contribute to the formation, maturation and plasticity of synapses remains elusive. Here we show that both astrocytes and neurons abundantly express neurexin-1, a presynaptic adhesion molecule that controls synaptic properties. Using super-resolution imaging, we demonstrate that presynaptic neuronal and astrocytic neurexin-1 form discrete nanoclusters at excitatory synapses. We find that distinct patterns of heparan sulfate modification and alternative splicing confer onto astrocytic and neuronal neurexin-1 different ligand specificities, thereby enabling compartment-specific signaling by neurexin-1. At hippocampal Schaffer-collateral synapses, deletion of neurexin-1 from either astrocytes or neurons did not alter synapse numbers, but differentially impaired synapse function. Neuronal neurexin-1 was essential for NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 was required for maturation of silent synapses, AMPA-receptor recruitment, and long-term potentiation. Thus, astrocytes and neurons surprisingly use the same synaptic adhesion molecule to control distinct synapse properties.

neuroscience↗

bioRxiv2017

Native KCC2 Interactome Reveals PACSIN1 As A Critical Regulator Of Synaptic Inhibition

KCC2 is a neuron-specific K+-Cl- cotransporter essential for establishing the Cl- gradient required for hyperpolarizing inhibition. KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to numerous human neurological disorders including epilepsy and neuropathic pain. Using unbiased functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with a diverse set of proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons significantly increases KCC2 expression and hyperpolarizes the reversal potential for Cl-. Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2.

neuroscience↗