Altered Dendritic Excitability and Cell Maturation of CA3 Pyramidal Neurons During Development in the SCN2A^A263V Genetic Epilepsy Model

Abstract

Gain of fUnction variants of the Nav1.2 sodium channel are strongly associated with various developmental disorders, as a common feature. Although previous studies in heterologous expression systems have identified the biophysical mechanism underlying the GOF, not well understood is how a GOF mutation alters cellular and synaptic properties during development. In this study, we studied the cellular excitability and dendritic integration in CA3 pyramidal neurons during early (PN10-PN14) and later (PN24-PN28) developmental stages in the SCN2A^A263V mouse model of genetic epilepsy using patch-clamp recordings and simultaneous glutamate iontophoresis. <br /> At PN10-PN14, the data show an abnormal transient somatic hyperexcitability in SCN2A^A263V mutant animals. During early development, CA3 dendrites from wt animals exhibited largely linear increases in EPSP amplitudes, whereas CA3 dendrites from SCN2A^A263V+/wt animals were capable of aberrant dendritic spikes (d-spikes). <br /> Next, we examined how dendritic morphology and excitability maturation changed following these aberrant dendritic spikes. At PN24-PN28, dendritic spikes maturated with a distinctive fast-rising phase in wt mice. In addition, most CA3 cells switched from an ‘athorny’ to a ‘thorny’ phenotype. However, CA3 dendrites in SCN2A mutant animals did not develop the characteristic fast d-spikes and remained primarily ‘athorny.’ <br /> These data suggest that aberrant dendritic hyperexcitability during early developmental stages alters the maturation of CA3 pyramidal neurons in the SCN2A^A263V model of genetic epilepsy.