Document text
Principal Investigator: Jaideep Kapur
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $496,351
Funding agency: National Institute of Neurological Disorders and Stroke
Project summary
Grand mal (great malady) seizures, now called generalized tonic clonic seizures (GTCS), are the most feared
seizures because they can cause death and injury. Repeated GTCSs are the leading risk factor for sudden
unexpected death in epilepsy (SUDEP), which is a leading cause of death in persons with epilepsy. GTCS also
leads to fractures and soft tissue injuries. It is long known that the motor cortex generates these seizures and
seizures modify the motor cortex. However, the cellular and molecular mechanisms of seizure-induced
reorganization of the motor cortex have not been studied. Furthermore, it is not known whether a GTCS makes
subsequent seizures more severe. We propose that GTCS enhance the excitability of a subset of motor cortex
pyramidal neurons by enhancing AMPA receptor mediated excitation. We found that GluA1 subunit of the
AMPA receptor was essential for expressing kindling-induced (grade 5) GTCS. We kindled mice lacking the
GluA1 subunit of AMPA receptors and their wild-type (WT) littermates using traditional kindling methods.
Whereas WT animals progressed to sustained convulsive GTCS (grade 4 & 5), but knockout animals neither
attained nor sustained GTCS, despite repeated stimulation. Furthermore, two (WT) animals died following
GTCS, while none of the KO animals died. In Aim 1, we propose to characterize the role of the GluA1 subunit
of AMPA receptors in sustaining repeated GTCSs using a combination of conditional knockout mice and
biochemical techniques in intrahippocampal kainate (IHK) and kindling models of TLE. Behavioral seizures
also become more intense when fully kindled animals were stimulated. Much larger volume of the cortex was
active during the 8th GTCS compared to the neocortical activation observed after the 3rd GTCS. Motor cortex
cell counts revealed that many more neurons in the motor cortex expressed c-fos in response to the fifth GTCS
compared to the first GTCS. In Aim 2 experiments, we propose to confirm and expand these findings. we will
compare cortical circuit activity maps and behavioral seizures in response to the first or fifth GTCS in kindling
and IHK TLE models. We compared the electrophysiological properties of motor cortex pyramidal neurons that
expressed c-fos in response to GTCSs with those of surrounding neurons that did not express c-fos and found
surprising differences. Motor cortex pyramidal neurons expressing c-fos were more excitable and
demonstrated enhanced AMPA receptor-mediated excitatory post synaptic currents. In Aim 3, we propose to
compare the excitability and excitatory transmission of layer 2/3 and layer 4/5 pyramidal neurons expressing c-
fos in response to a grade 5 kindled seizure using patch clamp recordings. These studies open a novel area of
epilepsy research, focusing on the effects of GTCS on the neocortex using a combination combine novel,
state-of-the-art techniques.
Terms: <3rd grade><8th grade><AMPA Receptors><Ammon Horn><Animal Model><Animal Models and Related Studies><Animals><Area><Behavioral><Biochemical><Brain><Brain Nervous System><Cause of Death><Cell Count><Cell Number><Cornu Ammonis><DNA Recombination><Data><Dentate Fascia><Development><Drugs><EEG><Electroencephalogram><Electroencephalography><Electrophysiology><Electrophysiology (science)><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><Estrogen Receptors><Exhibits><Experimental Models><FDA approved><FOS gene><Fascia Dentata><Fear><Fore-Brain><Forebrain><Fracture><Fright><G0S7><Generalized Status Epilepticus><Genetic Recombination><Glutamates><Gyrus Dentatus><Hippocampus><Image><Immediate-Early Genes><Injury><Investigation><KO mice><Knock-out Mice><Knockout Mice><L-Glutamate><Laser Electromagnetic><Laser Radiation><Lasers><Leptazole><Long-Term Potentiation><Longterm Potentiation><Maps><Mediating><Medication><Methods><Mice><Mice Mammals><Microscope><Modeling><Molecular><Monitor><Motor Cortex><Motor Skills><Murine><Mus><Neocortex><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Null Mouse><Patients><Pentamethylenetetrazole><Pentetrazole><Pentylenetetrazol><Pentylenetetrazole><Persons><Pharmaceutical Preparations><Population><Property><Prosencephalon><Proteins><Protooncogene FOS><Pyramidal neuron><Recombination><Refractory><Reporter><Research><Risk><Risk Factors><Role><SUDEP><Seizure Disorder><Seizures><Seminal><Slice><Soft Tissue Injuries><Status Epilepticus><Stimulus><Structure><Synapses><Synaptic><Techniques><Temporal Lobe Epilepsy><Testing><Tonic - clonic seizures><Transmission><bone fracture><c fos><c-fos Gene><c-fos Proto-Oncogenes><conditional knock-out><conditional knockout><dentate gyrus><developmental><drug/agent><eighth grade><electrophysiological><epilepsia><epileptogenic><experiment><experimental research><experimental study><experiments><glutamatergic><grand mal seizure><hippocampal><hippocampal pyramidal neuron><homotypical cortex><imaging><injuries><insight><isocortex><kainate><knock-out animal><knockout animal><locomotor learning><model of animal><motor learning><neocortical><neopallium><neuronal><novel><patch clamp><postsynaptic><promoter><promotor><response><skill acquisition><skill development><social role><sudden unexpected death in epilepsy><synapse><therapeutic target><third grade><transmission process><v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog>