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
Synaptic refinement in the thalamus
The refinement of neuronal connections, which consists of selective elimination and consolidation of synapses, is a key mechanism of neuroplasticity. Disruptions of this process, caused by either environmental or genetic factors or both, are thought to be a substrate for altered information processing and abnormal behaviors associated with common brain disorders including autism, epilepsy, mood and anxiety disorders, and schizophrenia. Elucidation of mechanisms of synaptic refinement may also provide opportunities for the development of new and improved treatments for neural injury.
The long-term goal of this project is to elucidate cellular and molecular mechanisms underlying synaptic refinement in the mammalian brain. The rodent whisker sensory system has been widely used in the studies of neuronal circuit formation and plasticity because of its topographic organization and accessibility for sensory manipulation. While synaptic refinement is thought to underlie activity-dependent plasticity, there has been little direct examination of synapse elimination and consolidation. 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, this process of refinement 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 propose to examine three hypotheses. (i) Sensory experience is critical for normal synaptic refinement. We will analyze the effects of sensory deprivation on synaptic refinement and examine the underlying molecular mechanisms using a combination of electrophysiological recording and gene expression analysis. (ii) The developmental switch of NMDA (N-methyl-D-aspartate) receptor composition plays an important role in synaptic refinement. We will use mice deficient of NMDA receptor subunits NR2A or NR2C or both to examine the role of NMDA receptor signaling in synaptic refinement. (iii) Signaling through adenylate cyclase 1 (AC1) is essential for normal synaptic refinement in the thalamus. We will analyze alterations of synaptic refinement in AC1-deficient mice and examine the molecular mechanisms involved. This work 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 the leading cause of child disability, there is no cure and only limited treatments for ASDs. Understanding the pathogenesis of ASDs is crucial for the development of novel treatments. We are investigating the role of a key molecule, methyl-CpG binding protein 2 (MeCP2), in brain development. Mutations in the Mecp2 gene are the primary cause of Rett syndrome (RTT), and they may also contribute to the pathogenesis of other ASDs. We have found that GABAergic transmission is significantly altered in Mecp2-knockout mice. Most interestingly, we have found that GABAeric transmission is altered in opposite directions in excitatory and inhibitory neurons. This is the first report of significant changes in inhibitory transmission in Mecp2 mutants (manuscript in preparation), underscoring the role of GABAergic system in RTT pathophysiology.
This research project has three parts. In Part 1, we will determine the changes in GABAergic transmission in the thalamus of Mecp2-null mice. We will focus on the thalamus because of its relatively simple organization and potential role in RTT pathogenesis. We will examine underlying cellular mechanisms through analysis of synaptic transmission, intrinsic firing properties and dendritic morphology. In Part 2, we will determine molecular mechanisms by which MeCP2 regulates GABAergic transmission. In Part 3, we will determine how MeCP2 deficiency in GABAergic neurons contributes to the pathophysiology of RTT through conditional knockout and conditional rescue of the Mecp2 gene.
Lab staff
Postdoctoral Fellow: Hao Wang, Ph.D., Wen Zhang, Ph.D.Research Assistants: Hong Liu, Ph.D., Matthew Peterson
Research Administrative Assistant: Annie McDonnell
Publication listings
Wang H, Liu H, Zhang ZW. 2011. Elimation of redundant synaptic inputs in the absence of synaptic strengthening. J. Neurosci. 31:16675-84
Wang H, Liu H, Storm D, Zhang ZW. 2011. Adenylate cyclase 1 promotes strengthening and experience-dependent plasticity of whisker relay synapses in the thalamus. J Physiol (London) Sep 19(Epub ahead of Print)
Zhang, ZW, Zak, JD, Liu H. 2010. MeCP2 is required for normal development of GABAergic circuits in the thalamus. J Neurophysiol 103(5):2470-2481. PMC2867574
Boumil R, Letts VA, Roberts MC, Lenz C, Mahaffey CL, Zhang ZW, Moser T, Frankel WN. 2010. A Missense Mutation in a Highly Conserved Alternate Exon of Synamin-1 Causes Epilepsy in Fitful Mice. Plos Genet 6(8):e10001046.
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. PMC26669449
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. PMC1779701
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.
