Topic: Nav1.2

Altered neuronal excitability in neurodevelopmental disorders can have profound implications for adult brain function. Understanding the critical time windows determining the clinical outcomes and lasting changes induced during these periods is therefore crucial. In our mouse model of developmental and epileptic encephalopathy (DEE) harboring a patient-derived Scn2a (p.A263V) mutation that results in a gain-of-function of Nav1.2 channels, Scn2a mutants exhibit a transient increase in excitability of hippocampal pyramidal neurons in vitro during the neonatal period. In vivo, homozygous Scn2a mu

Gain-of-function (GOF) variants of the Nav1.2 sodium channel have been strongly associated with a spectrum of developmental disorders, among which epilepsy is a commonly observed feature. Although prior studies conducted in heterologous expression systems have successfully delineated the biophysical mechanism underlying the GOF mutations, the comprehensive understanding of how a GOF mutation influences cellular and synaptic properties during the critical periods of development, and subsequently how these alterations impact cellular maturation, remains somewhat elusive.We studied the CA3 pyrami

SCN2A encodes the Nav1.2 voltage-gated sodium channel subunit, which is crucial for the initiation, propagation, and backpropagation of action potentials. During human and mouse brain development, Nav1.2 is the dominant axonal Nav isoform. Genetic SCN2A variants are associated with neurodevelopmental disorders such as epilepsy, ASD, ID, and schizophrenia. Nav1.2 gain-of-function variants have been shown to cause epilepsy and SUDEP, but the network changes driving epileptogenesis during development are not known. Given the dominant role of Nav1.2 during hippocampal development we hypothesize th

Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input-output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. Here, we identified a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. We discovered that PTPRN facilitates NaV1.2 sodium channel en

Repressor-element 1 silencing transcription factor (REST) is a zinc-finger-containing protein that has a vast array of target genes, including those involved in neuronal differentiation, neuronal activity, homeostatic plasticity, neuroinflammation and senescence.Understanding the endogenous mechanisms that control the level of REST is critical, if the protective expression of REST in neurodegeneration or aging were to become the focus of therapeutic approaches. Calcium is a signaling molecule that regulates neuronal activities as well as cellular processes such as autophagy leading to senescen

Maintaining Ca2+ homeostasis is extremely important for the nervous system. Fluctuations in extracellular Ca2+ concentration ([Ca2+]e) are very frequent, both under physiological and pathological conditions. Among extracellular calcium sensors, the Calcium-Sensing Receptor (CaSR), is a G-protein coupled receptor activated by [Ca2+]e and is ubiquitously expressed in the body. The CaSR is expressed in brain regions involved in memory and cognition, however the mechanisms by which CaSR regulates neuronal function remain unexplored.We therefore studied how CaSR regulates neuronal excitability in t