'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour.
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 NaV1.2(adult) mice expressing only the 'adult' NaV1.2, and compared the firing properties of pyramidal cortical neurons, as well as seizure susceptibility, between the NaV1.2(adult) 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 NaV1.2(adult) neurons and in seizure susceptibility of NaV1.2(adult) mice, supporting our hypothesis. At postnatal day 15 (P15), when 17% of the WT NaV1.2 is 'neonatal', the firing properties of NaV1.2(adult) and WT neurons converged. However, inhibitory postsynaptic currents in NaV1.2(adult) neurons were larger and the expression level of Scn2a mRNA was 24% lower compared with the WT. The enhanced seizure susceptibility of the NaV1.2(adult) mice persisted into adult age. The adult NaV1.2(adult) 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.
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia elena.gazina@florey.edu.au steven.petrou@florey.edu.au.
Elena V
EV
Gazina
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Bryan T W
BT
Leaw
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Kay L
KL
Richards
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Verena C
VC
Wimmer
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Tae H
TH
Kim
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Timothy D
TD
Aumann
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Travis J
TJ
Featherby
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Leonid
L
Churilov
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Vicki E
VE
Hammond
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia.
Christopher A
CA
Reid
The Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia Centre for Neural Engineering, University of Melbourne, Parkville VIC 3052, Australia elena.gazina@florey.edu.au steven.petrou@florey.edu.au.
Steven
S
Petrou
D000200:Action Potentials; D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010433:Pentylenetetrazole / Q000009:adverse effects; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000235:genetics*
D062551:NAV1.2 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D012333:RNA, Messenger; C000654500:Scn2a protein, mouse; D010433:Pentylenetetrazole