Our laboratory studies the development and function of neural circuits in the brain with goals to elucidate mechanisms of developmental brain disorder. We use a variety of experimental approaches, including electrophysiology, molecular genetics, anatomy, and behavior analysis. Two major research focuses are 1) cellular and molecular mechanisms underlying pruning and strengthening of excitatory synapses during early life, and 2) dysfunction of neural circuits in genetic models of autism spectrum disorders.
Neural Circuit Development in Health and Disease
Our overall goal is to unravel mechanisms of developmental brain disease, in particular autism spectrum disorders. We study functional maturation of brain circuits during normal development and in disease models.
Mechanisms of synaptic refinement
A common feature in the development of nervous systems is that immature neurons usually form synapses with a large number of target cells; many of these early connections are eliminated as the animal matures, while the remaining ones are strengthened. The seletive elimination (pruning) and strengthening of immature synapses, termed synaptic refinement, is essential for the development of neural circuits and behaviors. Disruptions of this process have been implicated in common brain disorders including autism and schizophrenia. Despite its importance, little is known about the cellular and molecular mechanisms of synaptic refinement in the brain. Our laboratory has made major contributions—both methodological and conceptual—to the study of synaptic refinement.
We have established a new model for studying refinement of excitatory synapses in the brain. Using patch-clamp recording in acute brain slices, we showed that the whisker relay synapse in the thalamus of the mouse undergoes extensive pruning and strengthening during the second week after birth. And this refinement process can be disrupted by sensory deprivation. This simple and quantitative model provides new opportunities for mechanistic analysis of synapse development.
Using this model we showed that adenylate cyclase 1, a major protein in cyclic AMP-dependent signaling in the brain of newborns, is implicated in synaptic strengthening but not pruning. This work provided the first indication that pruning is independent of synaptic strength. Next, we demonstrated that genetic deletion of AMPA type glutamate receptors, while completely abolished synaptic strengthening, had no effect on elimination of synaptic refinement. More recently, we examined the role of NMDA receptors in synaptic refinement using a genetic mosaic method. Our results strongly suggest that activation of NMDA receptors in postsynaptic neurons is required for both pruning and strengthening of immature synapses. Currently we are investigating the mechanisms by which NMDA receptors regulate pruning.
Neuronal mechanisms underlying Rett symdrome
The autism spectrum disorder Rett syndrome (RTT) is a pervasive brain disorder causing loss of motor and cognitive funtions, impaired social interactions, anxiety, and seizure in girls, with disease onset taking place between 6-18 months of age. Mutations in the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) and the loss of MeCP2 function in the brain are the primary causes of RTT. However, the underlying mechanisms are poorly understood. Through analysis of synaptic transmission in the thalamus of MeCP2 mutant mice, our laboratory provided strong evidence that hyperexcitation, caused by a reduction of inhibition, is a hallmark of early brain dysfunction in RTT. Recently we extended these studies to the prefrontal cortex, a brain region implicated in many phenotypes of RTT. Our results showed that the loss of MeCP2 from cortical excitatory neurons leads to a reduction of inhibition, hyperexcitation, and seizure. Our work underscores the role of GABAergic function in the pathophysiology of RTT and provides rationales for new treatments of RTT. Our current effort is focused on mechanisms by which MeCP2 regulates GABAergic function in the brain.
Postdoctoral Fellow: Wen Zhang, Ph.D.
Research Assistants: Hong Liu, Ph.D., Christopher McCarty
Research Administrative Assistant: Annie McDonnell
Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW. 2014. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation Seizures. J Neurosci. 34(7):2754-63. PMCID: PMC3921436.
Zhang ZW, Peterson M, Liu H. 2013. Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses. Proc Natl Acad Sci USA 110(3) 1095-1100. PMCID: PMC3549111
Wang H, Liu H, Zhang ZW. 2011. Elimation of redundant synaptic inputs in the absence of synaptic strengthening. J. Neurosci. 31:16675-84 PMCID: PMC3234497
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)589:5649-62. PMCID: PMC3249040
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. PMCID: not applicable
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.