Current Projects
Deciphering Brain Loci and Neural Circuit and Cellular Mechanisms Responsible for Absence Epilepsy
- Mutations of T-type Ca2+ channel Cav3.2 were found in patients with childhood absence epilepsy (Chen et al., 2003). Some of these mutations altered voltage-gating properties of the channel such that Ca2+ influx near resting membrane potentials is increased (Khosravani et al., 2004; Vitko et al., 2005). Using cell-type targeted expression of the mutated gene, we are investigating 1) whether mutations in this gene are sufficient to cause the disease, 2) whether the mutant gene causes disease through its effects in thalamic reticular or cortical pyramidal neurons, and 3) what cellular physiology is altered by the disease gene that might cause absence epilepsy.
- Embryonic and global deletion of the T-type Ca2+ channel Cav3.1 inhibits absence epilepsy (Kim et al., 2001; Song et al., 2004). Inhibition of Cav3.1 may represent a potent drug therapy to treat this disease with a low side effect profile. Using cell-type targeted deletion of the gene, we are investigating where Cav3.1 inhibition blocks the disease: the thalamus or the cortex.
Deciphering The Cellular Locus And Function of a Gene Mutated to Cause Autism
- Neuroligin 3 is mutated in some families with X-linked autism (Jamain et al., 2003). Neuroligin 1 over-expression induces synapse formation in cultured neurons (Scheiffele et al., 2000). However, neuroligin 3 may be primarily expressed by glia and therefore the function of this protein is unclear (Gilbert et al., 2001). To determine its function, we are applying methods to over-express or delete the protein in its native environment. We will then examine synaptic and other glial supported neuronal functions in these transgenic mice.
Deciphering The Cellular Locus and Function of a Gene Mutated to Cause Human Temporal Lobe Epilepsy
- We are investigating the effects of wild-type and mutant genes on cellular physiology of neurons embedded in their native brain circuitry.
Cellular Regulation of Burst and Tonic Firing in Thalamocortical Neurons
- Burst firing is increased in the thalamus in a variety of neurologic disease states including Parkinson’s disease, chronic pain, and epilepsy. Understanding how this firing mode is regulated and how it contributes to and controls the transmission of normal and pathologic signals will provide insight into these diseases.
