Current Projects

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.

15q11-13 duplications are the most common gene copy number variation consistently reported in autism patients (e.g., Glessner et al. Nature 2009). Inheritance of extra maternal allele copies is necessary to cause the disease. Increasing extra copy number (1-inv dupl 15, 2-idic(15), 4-hexasomy) results in an increasing severity of the symptoms. The specific gene or genes within this genomic segment responsible for autism remain undefined. Furthermore, the underlying neuronal circuit defects associated with these behavioral defects has not been examined. We are applying mouse genetics techniques to address these important questions.
Recent work has identified immune system disturbances in autism patients and their mothers. This includes perinatal infections (e.g., viral), maternal antibodies to fetal tissues, and ongoing innate immune system activity in CSF and brain tissues from autism patients. We are currently asking how activity of the mothers and infants immune system alters development and function of the brains neuronal circuitries.
Finally, we are developing a wide variety of new mouse models with the same genetic changes found in subsets of human autism patients.

We are investigating the effects of wild-type and mutant genes on cellular physiology of neurons embedded in their native brain circuitry.

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.