Developmental alterations in firing properties of hippocampal CA1 inhibitory and excitatory neurons in a mouse model of Dravet syndrome

AbstractDravet syndrome (Dravet) epilepsy begins with febrile seizures followed by worsening to refractory seizures, with some improvement and stabilization toward adolescence. The neuronal basis of Dravet is debatable, with evidence favoring reduced inhibition or enhanced excitation. Focusing on the firing properties of hippocampal CA1 pyramidal neurons and oriens-lacunosum moleculare (O-LM) interneurons, we provide a comprehensive analysis of the activity of both cell types through the febrile, worsening and stabilization stages. Our data indicate a temporary increase in the excitability of CA1 pyramidal neurons during the febrile stage, which is fully reversed by the onset of spontaneous seizures. In contrast, reduced function of O-LM interneurons persisted from the febrile through the stabilization stages, with the greatest impairment of excitability occurring during the worsening stage. Thus, both excitatory and inhibitory neurons contribute to Dravet, indicating complex and reciprocal pathophysiological neuronal changes during the different stages of the disease.Graphical abstract

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Synaptic and intrinsic mechanisms impair reticular thalamus and thalamocortical neuron function in a Dravet syndrome mouse model

10.1101/2021.09.03.458635 ◽

2021 ◽

Author(s):

Carleigh Studtmann ◽

Marek Ladislav ◽

Mackenzie A. Topolski ◽

Mona Safari ◽

Sharon A. Swanger

Keyword(s):

Mouse Model ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

List Type ◽

Cellular Mechanisms ◽

Gene Encoding ◽

Cortical Input ◽

Neuron Populations ◽

Firing Properties ◽

Synaptic Mechanisms

ABSTRACTThalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel NaV1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that NaV1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced intrinsic excitability in nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. NaV1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced ascending glutamatergic sensory input to VPL neurons, but not VPM neurons. In addition, glutamatergic cortical input to nRT neurons was reduced in Scn1a heterozygous mice, whereas cortical input to VPL and VPM neurons remained unchanged. These findings introduce input-specific alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in Dravet syndrome, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in Dravet syndrome and identifies new components of corticothalamic circuitry as potential therapeutic targets.HIGHLIGHTSGABAergic reticular thalamus neurons have impaired tonic and burst firing properties in a NaV1.1 haploinsufficiency mouse model of Dravet syndrome.NaV1.1 haploinsufficiency has opposing effects on spike firing in two distinct glutamatergic thalamocortical neuron populations.NaV1.1 haploinsufficiency alters glutamatergic synaptic connectivity in an input-specific manner in the thalamus.Dysregulation of both intrinsic and synaptic mechanisms contribute to imbalanced thalamic excitation and inhibition in this Dravet syndrome mouse model.

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Adolescent behavioral abnormalities in a Scn1a+/− mouse model of Dravet syndrome

Epilepsy & Behavior ◽

10.1016/j.yebeh.2019.106842 ◽

2020 ◽

Vol 103 ◽

pp. 106842

Author(s):

Dilara Bahceci ◽

Lyndsey Leigh Anderson ◽

Cassandra Veronica Occelli Hanbury Brown ◽

Cilla Zhou ◽

Jonathon Carl Arnold

Keyword(s):

Mouse Model ◽

Dravet Syndrome ◽

Behavioral Abnormalities

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Metabolomic signature of the Dravet syndrome: A genetic mouse model study

Epilepsia ◽

10.1111/epi.16976 ◽

2021 ◽

Author(s):

Nina Miljanovic ◽

Roelof Maarten van Dijk ◽

Verena Buchecker ◽

Heidrun Potschka

Keyword(s):

Mouse Model ◽

Dravet Syndrome ◽

Genetic Mouse Model ◽

Model Study

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Potentiating α 2 subunit containing perisomatic GABA A receptors protects against seizures in a mouse model of Dravet syndrome

The Journal of Physiology ◽

10.1113/jp277651 ◽

2019 ◽

Vol 597 (16) ◽

pp. 4293-4307 ◽

Cited By ~ 6

Author(s):

Toshihiro Nomura ◽

Nicole A. Hawkins ◽

Jennifer A. Kearney ◽

Alfred L. George ◽

Anis Contractor

Keyword(s):

Mouse Model ◽

Dravet Syndrome ◽

Gaba A

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Early Selective Vulnerability of Synapses and Synaptic Mitochondria in the Hippocampal CA1 Region of the Tg2576 Mouse Model of Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-121711 ◽

2013 ◽

Vol 34 (4) ◽

pp. 887-896 ◽

Cited By ~ 32

Author(s):

Marta Balietti ◽

Belinda Giorgetti ◽

Tiziana Casoli ◽

Moreno Solazzi ◽

Francesco Tamagnini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Selective Vulnerability ◽

Tg2576 Mouse ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Model Of Alzheimer’S Disease ◽

Hippocampal Ca1 ◽

Synaptic Mitochondria

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The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

Frontiers in Pharmacology ◽

10.3389/fphar.2021.675128 ◽

2021 ◽

Vol 12 ◽

Author(s):

Vaishali Satpute Janve ◽

Lyndsey L. Anderson ◽

Dilara Bahceci ◽

Nicole A. Hawkins ◽

Jennifer A. Kearney ◽

...

Keyword(s):

Mouse Model ◽

Drug Target ◽

Genetic Modifier ◽

Anticonvulsant Drug ◽

Dravet Syndrome ◽

Seizure Threshold ◽

Drug Resistant ◽

Spontaneous Seizures ◽

Temperature Thresholds ◽

Seizure Models

Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/− mouse model of DS. We found that cortical Trpv1 mRNA expression was increased in seizure susceptible F1.Scn1a+/− mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/− mice isogenic on 129S6/SvEvTac background, suggesting Trpv1 could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/− mice. Surprisingly, Trpv1 deletion had both pro- and anti-seizure effects. Trpv1 deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−; Trpv1+/− at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, Trpv1 deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/− model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.

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