'Neonatal' Na(v)1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour

摘要

Developmentally regulated alternative splicing produces 'neonatal' and 'adult' isoforms of four Na+ channels in human brain, Na(V)1.1, Na(V)1.2, Na(V)1.3 and Na(V)1.6. Heterologously expressed 'neonatal' Na(V)1.2 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 Na(V)1.2(adult) mice expressing only the 'adult' Na(V)1.2, and compared the firing properties of pyramidal cortical neurons, as well as seizure susceptibility, between the Na(V)1.2(adult) and wild-type (WT) mice at postnatal day 3 (P3), when the 'neonatal' isoform represents 65% of the WT Na(V)1.2. We show significant increases in action potential firing in Na(V)1.2(adult) neurons and in seizure susceptibility of Na(V)1.2(adult) mice, supporting our hypothesis. At postnatal day 15 (P15), when 17% of the WT Na(V)1.2 is 'neonatal', the firing properties of Na(V)1.2(adult) and WT neurons converged. However, inhibitory postsynaptic currents in Na(V)1.2(adult) neurons were larger and the expression level of Scn2a mRNA was 24% lower compared with the WT. The enhanced seizure susceptibility of the Na(V)1.2(adult) mice persisted into adult age. The adult Na(V)1.2(adult) mice also exhibited greater risk-taking behaviour. Overall, our data reveal a significant impact of 'neonatal' Na(V)1.2 on neuronal excitability, seizure susceptibility and behaviour and may contribute to our understanding of Na(V)1.2 roles in health and diseases such as epilepsy and autism.