Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy

Abstract

Voltage-gated sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.

Familial Hemiplegic Migraine

“…90 Deletion of the Na V 1.1␣ 1 gene had no discernible effect on Na ϩ currents in hippocampal pyramidal neurons of scna1a Ϫ/Ϫ mice, but led to 50% reduction of Na ϩ currents in inhibitory interneurons of heterozygote scna1a Ϫ/ϩ mice, suggesting that Na V 1.1 channels may be responsible for most or all of the Naϩ current in these interneurons, and for a minor fraction of the Na ϩ current in pyramidal cells. 89 GABAergic interneuron excitability was reduced in both scna1a Ϫ/Ϫ and scna1a Ϫ/ϩ mice, a finding that might underlie the epileptic phenotype of these mice. 89 This finding has important implications for understanding the pathophysiology of severe myoclonic epilepsy of infancy (SMEI), a rare disorder characterized by early-onset febrile seizures followed by intractable epilepsy, mental deterioration, and ataxia.…”

“…89 GABAergic interneuron excitability was reduced in both scna1a Ϫ/Ϫ and scna1a Ϫ/ϩ mice, a finding that might underlie the epileptic phenotype of these mice. 89 This finding has important implications for understanding the pathophysiology of severe myoclonic epilepsy of infancy (SMEI), a rare disorder characterized by early-onset febrile seizures followed by intractable epilepsy, mental deterioration, and ataxia. SMEI is caused by mutations in the SCNA1A gene, most of which are predicted to truncate Na V 1.1 channels, implying a complete loss of channel function; most of the missense mutations that have been tested functionally in heterologous expression systems produced nonfunctional human Na V 1.1 channels (although some mutations produced mixed defects, some implying gain-of-function and some loss-of-function of Na V 1.1 87 [and Heron et al 91 ]).…”

“…They are a relatively minor component of total brain Na V channels, but are broadly expressed in many types of neurons, including hippocampal and cortical pyramidal cells and inhibitory interneurons, where they appear specifically localized in the soma and proximal dendrites. 88,89 The specific somatodendritic localization implies that Na V 1.1 channels may play a key role in mediating dendritic excitability, an important component of synaptic signal processing. 90 Deletion of the Na V 1.1␣ 1 gene had no discernible effect on Na ϩ currents in hippocampal pyramidal neurons of scna1a Ϫ/Ϫ mice, but led to 50% reduction of Na ϩ currents in inhibitory interneurons of heterozygote scna1a Ϫ/ϩ mice, suggesting that Na V 1.1 channels may be responsible for most or all of the Naϩ current in these interneurons, and for a minor fraction of the Na ϩ current in pyramidal cells.…”

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…GABAergic interneurons are particularly sensitive to the loss of Nav1.1 in gene-targeted mice (Yu et al 2006, Ogiwara et al 2007, probably because Nav1.1 is expressed at higher levels in GABAergic interneurons than in glutamatergic pyramidal neurons. Hence, epileptogenic mutations may cause seizures because of decreased inhibition in neuronal circuits.…”

Novel Animal Models of Pediatric Epilepsy

“…It has been shown that the voltage-dependent activation or inactivation of sodium channels is unchanged [140]. However, the sodium current density in inhibitory interneurons in the hippocampus of NaV1.1 (+/−) and NaV1.1 (−/−) mice leads to a loss of sustained high-frequency firing of action potentials in hippocampal and cortical interneurons [138,140]. These abnormalities lead to hyperexcitability, which might explain epilepsy in patients with Severe myoclonic epilepsy of infancy (SMEI).…”