Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome

Abstract

Haploinsufficiency of the voltage-gated sodium channel Na V 1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of Na V 1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the Na V 1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome. D ravet syndrome (DS), also referred to as "severe myoclonic epilepsy in infancy," is a rare genetic epileptic encephalopathy characterized by frequent intractable seizures, severe cognitive deficits, and premature death (1-3). DS is caused by loss-of-function mutations in SCN1A, the gene encoding type I voltage-gated sodium channel Na V 1.1, which usually arise de novo in the affected individuals (4-7). Like DS patients, mice with heterozygous lossof-function mutations in Scn1a exhibit ataxia, sleep disorder, cognitive deficit, autistic-like behavior, and premature death (8)(9)(10)(11)(12)(13)(14). Like DS patients, DS mice first become susceptible to seizures caused by elevation of body temperature and subsequently experience spontaneous myoclonic and generalized tonic-clonic seizures (11). Global deletion of Na V 1.1 impairs Na + currents and action potential (AP) firing in GABAergic-inhibitory interneurons (8-10), and specific deletion of Na V 1.1 in forebrain interneurons is sufficient to cause DS in mice (13,15). These data suggest that the loss of interneuron excitability and resulting di...

Expecting the Unexpected: Lack of in Vivo Network Defects in an Scn1a Model of Dravet Syndrome

“…Their findings reflect previous results, showing hypoexcitability of PV+ and SOM+ DS neurons with no change in pyramidal neuron excitability (5,9). They also show that DS brain slices have faster propagation of ictal discharges.…”

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

“…Partial loss of Na v 1.1 function in parvalbumin-positive interneurons in the brain is sufficient to cause epilepsy (12,40). These neurons display high-frequency firing properties that exacerbate an Na v 1.1 deficit by driving remaining channels into the inactivated state.…”

“…In addition, an efficacious Na v 1.1 compound should target the appropriate gating transition to restore normal excitability patterns within a particular tissue. For example, neurons with a reduced complement of functional Na v 1.1 channels will be most prone to dysfunction during elevated or sustained neuronal firing, because the pool of available channels will be further reduced by usedependent accumulation of channels in inactivated states (12).…”

Dissecting the phenotypes of Dravet syndrome by gene deletion

“…EEG signals were processed off-line with a 0-70 Hz lowpass filter. Brain slices were prepared and electrophysiological studies were carried out as described (Rubinstein et al, 2014;Tai et al, 2014). Thermal induction of seizures was performed as described (Oakley et al, 2009.…”

“…Studies of mouse genetic models demonstrated that Dravet syndrome is caused by disinhibition due to reduced excitability of GABAergic inhibitory interneurons without a corresponding change in the activity of excitatory neurons (Yu et al, 2006;Ogiwara et al, 2007Ogiwara et al, , 2013Cheah et al, 2012;Dutton et al, 2012;Kalume et al, 2013;Rubinstein et al, 2014;Tai et al, 2014). Moreover, specific heterozygous deletion of Na v 1.1 in forebrain GABAergic interneurons leads to seizures, premature death Kalume et al, 2013;Ogiwara et al, 2013), cognitive deficits, and autistic features (Han et al, 2012), similar to those in patients with Dravet syndrome.…”