Our long term goal is to learn how an inherited gene error produces a specific pattern of epilepsy in the developing brain, to provide an exact description of seizure-induced plasticity within affected neural networks, and in this project period, to genetically dissect the intervening candidate networks and mechanisms using selective mutant gene expression in mouse models. Spike-wave (SW) absence seizures comprise a major category of inherited epilepsy in children. Mutant genes for this phenotype are known, and their effects on ion channel behavior and routes of convergence on downstream neuronal excitability in pacemaking circuitry are beginning to be clearly defined. We have detected a critical pathway converging on the elevation of thalamic T-type calcium currents, and further showed that isolated T-type channel overexpression in wild type mice promotes cortical SW discharges, illuminating a complex but shared plasticity pathway triggered by these genes. We now seek further definition of the precise timing, specific synaptic circuitry, and transcriptional mechanisms mediating inherited P/Q channel-linked network excitability defects in order to determine the reversability of these phenotypes.
In specific aim 1, new information from a conditional Cacna1a allele indicates that mice display SW epilepsy even when the P/Q type calcium current defects are engineered to appear with a delayed onset in the third postnatal week. This indicates that aberrant adult firing, not embryonic wiring, is a sufficient cause for this seizure phenotype, thereby demonstrating an important postnatal window of therapeutic opportunity.
In specific aims 2 and 3, we will narrow the circuitry required for inherited SW seizures by genetically ablating the P/Q channel gene in other subsets of neurons to determine whether these limbs of the thalamocortical loop are necessary or sufficient for SW phenotypes.
In specific aim 4 we will explore transcriptional mechanisms underlying the plasticity of thalamic t-type calcium currents. Since these currents are potentiated by a broad spectrum of neuronal injury, clarifying the mechanism underlying downstream calcium channelopathy remodeling is of central interest in understanding how to prevent or reverse this common form of inherited epilepsy.

Public Health Relevance

This project will determine how a mutation of a single gene causes a specific pattern of epilepsy in the brain, which brain circuits are involved, and when it appears during brain development. An inherited mechanism underlying the pathological transformation of thalamocortical network firing from normal rhythms to abnormal burst firing patterns during absence seizures will be isolated. These findings may lead to novel treatments for a common form of childhood epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029709-22
Application #
8449200
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Whittemore, Vicky R
Project Start
1991-09-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
22
Fiscal Year
2013
Total Cost
$461,656
Indirect Cost
$166,668
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Mark, Melanie D; Maejima, Takashi; Kuckelsberg, Denise et al. (2011) Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations. J Neurosci 31:4311-26

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