Epilepsy is one of the most common neurological disorders,
affecting nearly 2.5 million Americans - many of them children. Because
the hallmark feature of an epileptic brain is the occurrence of abnormal
electrical discharge (seizure), our laboratory is focused on intrinsic,
synaptic and non-synaptic mechanisms that regulate neuronal excitability.
By studying animal models of epilepsy and tissue obtained from patients
undergoing surgery for intractable epilepsy we hope to obtain a better
understanding of the neurobiological basis of epilepsy. Techniques
include the use of in vitro brain slices for patch-clamp recording
of membrane properties and synaptic function; molecular analysis
of gene expression using in situ hybridization; immunohistochemical
and morphological studies of neuronal structure and protein expression;
pharmacological analysis of seizure modulation in knockout mice;
and a forward-genetic screening strategy to uncover novel epilepsy-related
gene mutations. Our current research interests lie in three general
areas: • Epilepsy Associated with a Malformed Brain: The methylazoxymethanol-exposed
(MAM) rat model, developed in our laboratory, mimics abnormal neuronal
migration disorders observed in the cortex and hippocampus of children
with intractable epilepsy. MAM rats with hippocampal heterotopia
exhibit rare spontaneous seizures, are more susceptible to induced
seizures, and are resistant to standard anticonvulsant medications.
We have also demonstrated that heterotopic cell clusters (i) contain "epileptic" neurons
capable of acting as burst generators in vitro, (ii) exhibit a
neocortical phenotype, and (iii) lack a functional Kv4.2 fast-transient
type K channel. Similar studies using animal models of Type-I Lissencephaly
and Tuberous Sclerosis Complex are underway. As a correlate to
animal studies, we also perform research using tissue samples obtained
during resective surgery.
• Seizures and Seizures Resistance in Zebrafish: Genetic
screening approaches wherein mutagen treatment introduces random
mutations into the genome and resultant mutants are recovered in
subsequent generations is a powerful and un-biased method to identify
epilepsy genes. We have developed novel electrophysiological, molecular
and behavioral techniques to initiate and characterize epileptic
seizure activity in zebrafish. A forward-genetic mutagenesis screen
(in collaboration with Herwig Baier) to isolate and characterize "seizure-resistant" mutants
is currently underway.
• Anticonvulsant Strategies: Neuropeptides, Astrocytes
and Stem Cells: Additional areas of investigation in the laboratory
are focused on novel anticonvulsant strategies. Specifically, we
have studied the anticonvulsant properties of neuropeptide Y (an
endogenous modulator of presynaptic excitation) and furosemide
(a common diuretic). Each of these agents exhibits powerful anticonvulsant
actions in vitro and in vivo. In a new research direction, we are
beginning to explore the potential of embryonic progenitor cells
(in collaboration with Arturo Alvarez-Buylla) to develop functional
and "anticonvulsant" neurons following transplantation.
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Biomedical Sciences (BMS) Graduate Program
