Publication Date:
2015-02-10
Description:
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’ Na V 1.2 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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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