Inhibitory interneurons synthesize GABA and play a critical regulatory role in the central nervous system. Recent observations suggest that development of these interneurons requires a family of Dlx transcription factors. In studies from our laboratory (Cobos et al. 2005), it was demonstrated that mice lacking Dlx1 progressively lose a sub-class of cortical and hippocampal interneurons resulting in reduced synaptic inhibition and epilepsy. This novel model of interneuron-deficient, late-onset epilepsy offers a unique opportunity to precisely define the role of interneurons in epileptogenesis, and ultimately test therapeutic interventions to interrupt or abrogate this process. In response to recent NINDS """"""""benchmarks"""""""", we here propose experiments that will examine how Dlx1 deficiency (and subsequent interneuron loss) alters network excitability, and test a potential therapeutic intervention using GABA progenitor cells. Techniques will involve use of acute brain slices maintained in vitro, and application of visualized patch clamp methods to study the physiological function of hippocampal interneurons and their associated circuits. Video-EEG monitoring and cell grafting techniques will also be applied.
Three specific aims are proposed: (i) determine whether Dlx1 is required for interneuron function, (ii) determine whether synaptic input to surviving interneurons is disrupted in Dlx1 mutant mice, and (iii) determine whether GABA progenitor cell grafts reduce seizure activity in Dlx1 mutant mice. Our results promise to provide critical information about the role of interneurons in epilepsy and may provide a direct demonstration of the potential for GABA progenitor cells to treat seizures.
Epilepsy is a common neurological disorder afflicting nearly 3 million Americans. Loss or reduction of inhibitory synaptic transmission in hippocampal and cortical circuits is one potential mechanism resulting in the emergence of epilepsy. Using a mouse mutant lacking inhibitory nerve cells, and a cell grafting strategy to generate new inhibitory nerve cells, we will examine the mechanisms underlying epilepsy and a potential treatment.
| Howard, MacKenzie Allen; Rubenstein, John L R; Baraban, Scott C (2014) Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo. Proc Natl Acad Sci U S A 111:492-7 |
| Jones, Daniel L; Howard, MacKenzie A; Stanco, Amelia et al. (2011) Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons. J Neurophysiol 105:1984-91 |
