Overview
Our research focuses on the development of the mammalian brain. Proper function of the brain relies on highly sophisticated networks composed of specialized cells, called neurons, interconnected in specific ways. We are working on two related projects to discover how these networks develop and change at the cellular and molecular levels and how defects in these processes contribute to brain disorders such as autism and schizophrenia.
Scientific report
Synapse Development and Plasticity
The mammalian brain, with billions of neurons and trillions of synapses, is by far the most complex organ of the body. Proper function of the brain relies on highly sophisticated neural networks that are composed of distinct groups of neurons interconnected in specific ways. My long-term goal is to study cellular and molecular mechanisms that are critically involved in the formation and plasticity of neural networks in the mammalian brain, and to contribute to the research on brain disorders associated with developmental defects. We currently focus on two related projects: 1) developmental remodeling of glutamatergic synapses; and 2) the role of MeCP2 in the development of GABAergic synapses.
Synapse Refinement in the Thalamus
The refinement of neuronal connections, which consists of selective elimination and consolidation of synapses, is a key mechanism of neural plasticity. Disruptions of this process, caused by either environmental or genetic factors or both, are thought to underlie altered information processing and abnormal behaviors associated with common brain disorders including autism, epilepsy, mood and anxiety disorders, and schizophrenia. Elucidation of the mechanisms of synaptic refinement may also provide opportunities for the development of new and improved treatments for neural injury.
We have developed a model for studying synaptic refinement at the single-cell level using the whisker sensory relay synapse in the thalamus of the mouse. We have found that extensive synaptic refinement occurs at this synapse during early life, and most interestingly, that the refinement process is disrupted by sensory deprivation. We believe that this model provides an excellent opportunity to study mechanisms of synaptic refinement in the brain. By combining cellular physiology with molecular genetic analysis in the mouse, we will determine the role of sensory experience in synapse refinement and define the molecular mechanisms involved. This research will provide new insights into the complex interactions between genes and the environment.
MeCP2 and GABAergic transmission
Autism-spectrum diseases (ASDs) are a group of developmental disorders defined by significant impairment in social interaction and other cognitive functions. About 1 in 150 children in the U.S. has an ASD. While ASDs are the leading cause of child disability, there is no cure and only limited treatments for them. Understanding the pathogenesis of ASDs is crucial for the development of novel treatments. We are investigating the role of a key transcriptional repressor, methyl-CpG binding protein 2 (MeCP2), in brain development. MeCP2 is highly expressed in the brain. Mutations in the Mecp2 gene are the primary cause of Rett syndrome, an ASD with profound clinical consequences, and may also contribute to the pathogenesis of other ASDs. We have found that GABAergic transmission is significantly altered in Mecp2-knockout mice. Our findings suggest a role for MeCP2 in the development of inhibitory synapses in the brain, and underscore a role of the GABAergic system in the pathophysiology of Rett syndrome. Through a combination of cellular physiology, molecular biology and mouse genetics, we are investigating how MeCP2 regulates the development of GABAergic synapses and the functional implications of these actions. This research will provide new insights into the causes of autism-spectrum diseases and may lead to the development of new and improved treatments.
Lab staff
Postdoctoral Fellow: Hao Wang, Ph.D.Research Assistant I: Hong Liu, Ph.D., Joseph Zak, B.S.
Research Administrative Assistant: Patricia Cherry
Publication listings
Echeverry S, Shi XQ, Haw A, Liu H, Zhang ZW, Zhang J (2009) Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Molecular Pain 5:16.
Wang H, Zhang ZW. 2008. A critical window for experience-dependent plasticity at whisker sensory relay synapse in the thalamus. J Neurosci 28(50):13621-13628.
Arsenault D, Zhang ZW. 2006. Developmental remodeling of the lemniscal synapse in the ventral basal thalamus of the mouse. J Physiol 573:121-132.
Zhang ZW. 2006. Developmental refinement in the mammalian thalamus. Crit Rev Neurobiol 18(1-2):49-59.
Zhang ZW. 2006. Postnatal development of the mammalian neocortex: Role of activity revisited. Can J Neurol Sci 33:158-169.
Timofeeva E, Dufresne C, Sik A, Zhang ZW, Deschenes M. 2005. Cholinergic modulation of vibrissal receptive fields in trigeminal nuclei. J Neurosci 25:9135-9143.
Zhang ZW, Arsenault D. 2005. Gain modulation by serotonin in layer 5 pyramidal neurons of the rat prefrontal cortex. J Physiol 566:379-394.
Zhang ZW . 2004. Maturation of layer 5 pyramidal neurons in the rat prefrontal cortex: Intrinsic properties and synaptic function. J Neurophysiol 91:1171-1182.
Zhang ZW. 2003. Serotonin induces tonic firing in layer V pyramidal neurons of rat prefrontal cortex during postnatal development. J Neurosci 23:3373-3384.
