ALTERED DENDRITIC EXCITABILITY AND CELL MATURATION OF CA3 PYRAMIDAL NEURONS DURING DEVELOPMENT IN THE SCN2AA263V GENETIC EPILEPSY MODEL
1 Institute of Experimental Epileptology and Cognition Research (IEECR), University of Bonn Faculty of Medicine
2 German Center for Neurodegenerative Diseases (DZNA), Bonn, Germany
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 pyramidal cell morphology as well as cellular & dendritic excitability during early postnatal (PN10-PN14) and later postnatal (PN24-PN28) developmental stages in the Scn2aA263V mouse model of genetic epilepsy using patch clamp recordings and simultaneous glutamate iontophoresis. During development in wt animals, we found that CA3 cells mature into a heterogenous population that switches from primarily ‘athorny’ in early development to a primarily ‘thorny’ cell phenotype in later development. In Scn2aA263V mutant animals, however, CA3 cells did not switch to a primarily ‘thorny’ phenotype, remaining mostly ‘athorny’, suggesting an altered cellular maturation. We next investigated how somatic and dendritic excitability developed over CA3 pyramidal cell maturation. During early development, CA3 dendrites from Scn2aA263V+/wt animals were capable of aberrant dendritic spikes that were not seen in wt animals. In addition, SCN2AA263V+/wt animals exhibited somatic hyperexcitability. during early development that normalized later in development. Taken together, our data indicate that aberrant hyperexcitability observed during early developmental stages may alter the maturation of CA3 pyramidal neurons in the SCN2AA263V model of genetic epilepsy.