Z. Josh Huang
Ph.D., Brandeis University, 1994
Development and function of the GABAergic inhibitory circuitry in neocortex
Cortical circuits; mouse genetics; developmental plasticity, neurogenomics, autism
In mammalian neocoertex, the delicate balance and functional architecture of neural circuits are achieved through a rich repertoire of inhibitory control mechanisms. A key obstacle to understanding inhibitory circuitry is the diversity of GABAergic interneurons: how are diverse cell types generated and assembled into stereotyped local circuits, and how do they differentially contribute to circuit operations underlying functions ranging from perception to cognition? Using mouse genetic engineering, intersectional targeting, and lineage tracing, we have generated over 20 Cre knockin driver lines that targeted major classes of GABAergic neurons. Genetic targeting integrates a suite of modern technologies (e.g. live imaging and optogenetics) for reliable identification, monitoring, and manipulation of GABAergic cell types. This strategy allows us to systematically study GABAergic circuitry from cell fate specification, connectivity, to function in networks and behavior.
As an example, chandelier cell (ChC) is the most distinctive class of cortical interneurons that exclusively innervate pyramidal cells at axon initial segments, the site of action potential generation, thus may exert decisive control over the firing of neuron populations. Because of their exceptional stereotypy and specificity, our genetic capture of ChCs establishes an experimental paradigm for a comprehensive study, from their origin to function. Analysis of ChCs not only provides a key entry point to understanding the assembly and function of cortical circuitry but also will shed light into the pathogenic mechanisms of neuropsychiatric disorders such as schizophrenia, autism. We use a variety of integrated techniques and preparations, including molecular genetics, viral tracing, two-photon imaging, electrophysiology, and neurogenomics.
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Taniguchi, H., Lu, J., and Huang, Z,J. 2013. The Spatial and Temporal Origin of Chandelier Cells in Mouse Neocortex. Science 339: 70–74.
He, M., Liu, Y., Wang, X., Zhang, M.Q., Hannon, G.J., and Huang, Z.J. 2012. Cell-type-based analysis of microRNA profiles in the mouse brain. Neuron 73: 35–48.
Taniguchi, H., He, M., Wu, P., Kim, S., Paik, R., Sugino, K., Kvitsani, D., Fu, Y., Lu, J., Lin, Y., Myoshi, G., Shima, Y., Fishell, G., Nelson, S., and Huang, Z.J. 2011. A Resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71: 995–1013.
DiCristo, G., Chattopadhayaya, B., Kuhlman, S., Fu, Y., Wu, C.Z., Rutishausser, U., Maffei., L., and Huang, Z.J. 2007. Activity-dependent PSA expression regulates inhibitory maturation and onset of critical period plasticity. Nat. Neurosci. 10: 1569–1577.
Ango, F., DiCristo, G., Higashiyama, H., and Huang, Z.J. 2004. An ankyrin-based subcellular gradient of the immunoglobulin cell adhesion protein neurofascin specifies GABAergic innervation at Purkinje axon initial segment. Cell 119: 257–272.