Regulation of GABAergic inhibition in development and mental disorders
The majority of fast synaptic inhibition in the CNS is mediated by GABA type A neurotransmitter receptors (GABAARs) which are Cl- selective ligand-gated ion channels composed of 5 subunits (from up to 17 different subunits), with differential expression across brain regions, cell types and subcellular localization. Our broad goal is to understand the impact of dynamically regulated GABAAR surface levels and distribution in normal development and pathological conditions.
We utilize molecular, biochemical and imaging based methods to investigate:
1) Modulation of GABAAR trafficking and synaptic inhibition by benzodiazepines (BZ) and other GABAergic agents. The goal of this project is to identify the molecular mechanism underlying tolerance to these front line treatments for anxiety, insomnia, schizophrenia and epilepsy.
2) The role of GABAergic signaling in CNS development and plasticity. The majority of excitatory synapses in the brain are located at the end of dendritic spines, small protrusions from neuronal processes, with neighboring GABAergic synapses predominantly located on dendritic shafts. Alterations in the ratio of inhibitory/excitatory signaling is implicated in neurodevelopmental disorders such as autism. Our goal is to understand the contribution of GABAergic inhibition to dendritic spine morphology, dendritic arborization and circuit formation.
Jacob, T.C., Michels, G., Silayeva, L., Haydon, J., Succol, F. and Moss, S.J. Benzodiazepine treatment induces subtype specific changes in GABA-A receptor trafficking and decreases synaptic inhibition (accepted at PNAS October 2012).
Jacob, T.C., Wan, Q., Vithlani, M., Saliba, R.S., Succol, F., Pangalos, M.N. and Moss, S.J. GABA(A) receptor membrane trafficking regulates spine maturity. Proceedings of the National Academy of Sciences of the United States of America, 106, 12500-12505, 2009.
Jacob, T.C., Moss, S.J. and Jurd, R. GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nature Reviews, 9, 331-343, 2008.
Saliba, R.S., Michels, G., Jacob, T.C., Pangalos, M.N. and Moss, S.J. Activity-dependent ubiquitination of GABA(A) receptors regulates their accumulation at synaptic sites. J Neurosci. 27, 13341-13351, 2007.
Jacob, T.C. *, Bogdanov, Y.D.*, Magnus, C., Saliba, R.S., Kittler, J.T., Haydon, P.G. and Moss, S.J. Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors. J Neurosci 25, 10469-10478, 2005.