'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour

Abstract

Developmentally regulated alternative splicing produces 'neonatal' and 'adult' isoforms of four Na+ channels in human brain, NaV1.1, NaV1.2, NaV1.3 and NaV1.6. Heterologously expressed 'neonatal' NaV1.2 channels are less excitable than 'adult' channels; however, functional importance of this difference is unknown. We hypothesized that the 'neonatal' NaV1.2 may reduce neuronal excitability and have a seizure-protective role during early brain development. To test this hypothesis, we generated NaV1.2adult mice expressing only the 'adult' NaV1.2, and compared the firing properties of pyramidal cortical neurons, as well as seizure susceptibility, between the NaV1.2adult and wild-type (WT) mice at postnatal day 3 (P3), when the 'neonatal' isoform represents 65% of the WT NaV1.2. We show significant increases in action potential firing in NaV1.2adult neurons and in seizure susceptibility of NaV1.2adult mice, supporting our hypothesis. At postnatal day 15 (P15), when 17% of the WT NaV1.2 is 'neonatal', the firing properties of NaV1.2adult and WT neurons converged. However, inhibitory postsynaptic currents in NaV1.2adult neurons were larger and the expression level of Scn2a mRNAwas 24% lower compared with the WT. The enhanced seizure susceptibility of the NaV1.2adult mice persisted into adult age. The adult NaV1.2adult mice also exhibited greater risk-taking behaviour. Overall, our data reveal a significant impact of 'neonatal' NaV1.2 on neuronal excitability, seizure susceptibility and behaviour and may contribute to our understanding of NaV1.2 roles in health and diseases such as epilepsy and autism.