Altered Firing Rates and Patterns in Interneurons in Experimental Cortical Dysplasia

Zhou, Fu-Wen; Roper, Steven N.

doi:10.1093/cercor/bhq234

Cited by 35 publications

(35 citation statements)

References 73 publications

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“…The functional roles of SST interneurons in epilepsy and other neurological diseases are complex and less well-established than for PV interneurons. Reduction in excitability in both SST interneurons and PV interneurons is observed in a rat model of cortical dysplasia (46). Mice lacking the transcription factor Dlx1 display subtype-specific reduction of excitability in cortical SST interneurons and calretinin-expressing interneurons, but not in PV interneurons, and these mice showed generalized electrographic seizures (47).…”

Section: Sodium Currents In Cell Bodies Of Cortical Gabaergic-inhibitorymentioning

confidence: 99%

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

Tai

Abe

Westenbroek

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

234

215

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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...

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Section: Sodium Currents In Cell Bodies Of Cortical Gabaergic-inhibitorymentioning

confidence: 99%

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

Tai

Abe

Westenbroek

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

234

215

View full text Add to dashboard Cite

show abstract

“…However, changes in membrane excitability of neurons have consistently been described in neuronal migration disorders (Castro et al, 2001;Trotter et al, 2006;George and Jacobs, 2011;Zhou and Roper, 2011) and could contribute to abnormal network excitability. Therefore, we first obtained somatic whole-cell current-clamp recordings from granule cells of wild-type controls (n ϭ 14) and age-matched LIS1 mutants (n ϭ 14) to compare passive membrane and intrinsic firing properties.…”

Section: Intrinsic Excitability Of Mature Granule Cellsmentioning

confidence: 99%

LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

et al. 2012

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Type I lissencephaly, a neuronal migration disorder characterized by cognitive disability and refractory epilepsy, is often caused by heterozygous mutations in the LIS1 gene. Histopathologies of malformation-associated epilepsies have been well described, but it remains unclear whether hyperexcitability is attributable to disruptions in neuronal organization or abnormal circuit function. Here, we examined the effect of LIS1 deficiency on excitatory synaptic function in the dentate gyrus of hippocampus, a region believed to serve critical roles in seizure generation and learning and memory. Mice with heterozygous deletion of LIS1 exhibited robust granule cell layer dispersion, and adult-born granule cells labeled with enhanced green fluorescent protein were abnormally positioned in the molecular layer, hilus, and granule cell layer. In whole-cell patch-clamp recordings, reduced LIS1 function was associated with greater excitatory synaptic input to mature granule cells that was consistent with enhanced release probability at glutamatergic synapses. Adult-born granule cells that were ectopically positioned in the molecular layer displayed a more rapid functional maturation and integration into the synaptic network compared with newborn granule cells located in the hilus or granule cell layer or in wild-type controls. In a conditional knock-out mouse, induced LIS1 deficiency in adulthood also enhanced the excitatory input to granule cells in the absence of neuronal disorganization. These findings indicate that disruption of LIS1 has direct effects on excitatory synaptic transmission independent of laminar disorganization, and the ectopic position of adult-born granule cells within a malformed dentate gyrus critically influences their functional maturation and integration.

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“…In support of this conclusion, a recent examination of interneuron firing rates in a model of cortical dysplasia reported that reductions in glutamatergic drive of interneurons were correlated with reduced spontaneous firing rates of these cells (Zhou and Roper 2010).…”

Section: Discussionmentioning

confidence: 85%

Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons

Jones

Howard

Stanco

et al. 2011

Journal of Neurophysiology

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Dlx transcription factors are important in the differentiation of GABAergic interneurons. In mice lacking Dlx1, early steps in interneuron development appear normal. Beginning at ∼1 mo of age, primarily dendrite-innervating interneuron subtypes begin to undergo apoptosis in Dlx1−/− mice; this is accompanied by a reduction in GABAergic transmission and late-onset epilepsy. The reported reduction of synaptic inhibition is greater than might be expected given that interneuron loss is relatively modest in Dlx1−/− mice. Here we report that voltage-clamp recordings of CA1 interneurons in hippocampal slices prepared from Dlx1−/− animals older than postnatal day 30 (>P30) revealed a significant reduction in excitatory postsynaptic current (EPSC) amplitude. No changes in EPSCs onto interneurons were observed in cells recorded from younger animals (P9–12). Current-clamp recordings from interneurons at these early postnatal ages showed that interneurons in Dlx1−/− mutants were immature and more excitable, although membrane properties normalized by P30. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, caspase-3, and NeuN staining did not reveal frank cell damage or loss in area CA3 of hippocampal sections from adult Dlx1−/− mice. Delayed interneuron maturation may lead to interneuron hyperexcitability, followed by a compensatory reduction in the strength of excitatory transmission onto interneurons. This reduced excitation onto surviving interneurons, coupled with the loss of a significant fraction of GABAergic inputs to excitatory neurons starting at P30, may underlie cortical dysrhythmia and seizures previously observed in adult Dlx1−/− mice.

show abstract

Altered Firing Rates and Patterns in Interneurons in Experimental Cortical Dysplasia

Cited by 35 publications

References 73 publications

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

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

LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons

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