Altered Function of the SCN1A Voltage-gated Sodium Channel Leads to γ-Aminobutyric Acid-ergic (GABAergic) Interneuron Abnormalities

Abstract

Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS؉), 7 severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS؉ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a RH/RH mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a RH/؉ heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a RH/؉ and Scn1a RH/RH mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders.

Gene expression analysis in the parvalbumin‐immunoreactive PV1 nucleus of the mouse lateral hypothalamus

“…Some of the genes expressed in the PV1 nucleus (listed in Table 1) are known to occur in subclasses of GABAergic neurons. These include: Pitx2 (Skidmore et al, 2008;Waite et al, 2011), Scrt (Marin & Nieto, 2006), Scn1a (Ogiwara et al, 2007;Martin et al, 2010), Gfra1 (Pozas & Ibanez, 2005;Canty et al, 2009), Lynx2 (Dessaud et al, 2006 and Tmem163 (Burré et al, 2007). Of the tested genes, only Lynx2, Slc17a6 and Adcyap1 were expressed exclusively in the glutamatergic neurons of the PV1 nucleus.…”

Pain Mechanisms and Centralized Pain in Temporomandibular Disorders

“…nonspecific orofacial pain with SNPs of the SCN1A gene, which is implicated in the initiation and propagation of action potentials in afferent nerves and may impair gamma-aminobutyric acid (GABA)ergic interneuron function in the central nervous system, altering inhibitory tone (Martin et al 2010); 2. general psychological symptoms and 1 SNP of the COX1 gene, a strong regulator of central neuroinflammation (Choi et al 2009); and 3. temporal summation of heat pain sensation with an SNP of the MPDZ gene, which encodes proteins related to G protein-coupled receptors for neurotransmitters, including GABA (Balasubramanian et al 2007). …”

Epileptic Channelopathies and Dysfunctional Excitability - From Gene Mutations to Novel Treatments

“…Loss of one SCN1A copy led to a reduction in action potential number, frequency and amplitude in the interneurons (Yu et al, 2006). Similarly, studies in several animal models carrying nonsense or missense mutations in SCN1A show impaired interneuron function (Martin et al, 2010;Mashimo et al, 2010;Ogiwara et al, 2007;Tang et al, 2009). These studies indicate that functional loss of one copy of SCN1A reduces the inhibitory function of GABAergic interneurons and enhances the excitability of downstream synaptic targets, thereby predisposing to epileptic seizures.…”