Our laboratory studies the development of inhibitory circuits in the brain. As in a conventional electrical circuit, the brain uses both positive and negative components to amplify desirable signals while maintaining the overall stability of the system. An outstanding question in neurobiology is how the balance between excitation and inhibition is established and maintained. The underlying molecular mechanisms are not well understood, but inhibitory neurons and their connections, which are readily modified by activity, are likely to play a critical role. Impaired inhibition has been implicated in many brain disorders, including epilepsy, anxiety disorders, schizophrenia and autism.
A key ingredient of the answer to this question is the regulation of gene expression in response to neural activity. This allows a neuron to respond to activity by activating or repressing genetic programs, in order to adjust the number and strength of excitatory and inhibitory synapses according to the level of network activity. Using DNA microarrays to identify the transcription program regulated by neuronal activity, a bHLH-PAS transcription factor Npas4 was discovered to be a key regulator of inhibitory synapse development (Lin et al., Nature 2008). Npas4 is induced specifically by synaptic activity and the level of Npas4 dictates the level of inhibition: reducing Npas4 expression by RNAi or mouse gene disruption leads to a decrease in the number of inhibitory synapses, while over-expression of Npas4 increases it. This work revealed a novel transcriptional pathway involved in activity-regulated GABAergic synapse development and gives us a unique opportunity to unravel the mechanism by which neural activity regulates inhibitory synapses and the balance between excitation and inhibition.
Our laboratory builds on this work and focuses on understanding how neuronal activity regulates the development and function of both inhibitory synapses and inhibitory neurons. We use forward genetics to identify transcription programs that are important for the development of inhibitory circuits, followed by a combination of molecular, biochemical, electrophysiological and mouse genetic approaches to extend gene discovery to an in-depth understanding of the molecular mechanisms underlying inhibitory circuit development and function. Our research will address fundamental questions in neuroscience and identify potential therapies for neurological disorders.
Lin, Y., Bloodgood, B.L., Hauser, J.L., Lapan, A.D., Koon, A.K., Kim, T.K., Hu, L.S., Malik, A.N. & Greenberg, M.E. (2008). Activity-dependent regulation of GABAergic synapse development by Npas4. Nature, in press.
Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science, 321, 218-223.
Paradis, S., Harrar, D.B., Lin, Y., Koon, A.K., Hauser, J.L., Griffith, E.C., Zhu, L., Brass, L.F., Chen, C. & Greenberg, M.E. (2007). An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development. Neuron 53, 217-232.
Lin, Y., Fletcher, C.M., Zhou, J., Allis, C.D. & Wagner, G. (1999). Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A. Nature 400, 86-89.