The Zhang Lab

Zhong-wei Zhang

Principal Investigator: Zhong-wei Zhang, Ph.D.

The Jackson Laboratory
Bar Harbor, ME

Studying the development and function of neural circuits and dysfunctions related to autism spectrum disorders.

Full Scientific Report

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 selective 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 abolishing 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 demonstrated 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 synaptic refinement.

Neuronal mechanisms underlying autism spectrum disorder

Autism spectrum disorder (ASD) is a group of brain developmental disorders characterized by impaired social interaction, verbal and nonverbal communication, restricted interest and repetitive behaviors. Genetic defect is a major cause of ASD, and a rapidly growing number of genes have been implicated. How genetic mutations cause ASD remains unknown, and the answer to this question is critical for development of treatment for ASD. By investigating mice carrying mutations found in ASD, we aim to elucidate mechanisms underlying ASD.

We have been focused on the autism spectrum disorder Rett syndrome, a pervasive brain disorder causing loss of motor and cognitive functions, impaired social interactions, anxiety and seizure in girls. 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 Rett syndrome. 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 Rett syndrome. Recently we extended these studies to the neocortex, a brain region implicated in many phenotypes of Rett syndrome. 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 Rett syndrome and provides rationales for new treatments of Rett syndrome.