Neural communication occurs via the release of neurotransmitter-containing vesicles at synaptic contact sites. Depending on their availability for release, synaptic vesicles are organized in several functionally distinct pools. The proper function of synapses relies on an efficient vesicle cycling program to maintain these vesicle pools and sustain neurotransmitter release. Despite extensive research on synaptic function, the basic mechanisms of vesicle cycling remain poorly understood due to the relative inaccessibility of central synapses to conventional recording techniques. To address these limitations we developed a novel nanometer-resolution imaging approach to directly visualize and study, at a single-vesicle level, the vesicle cycling events within individual central synapses (Peng at al, Neuron 2012). We are now using these optical measurements to address several fundamental aspects of synaptic vesicle cycling such as the organization and function of different vesicle pools, and the dynamics of vesicle mobilization, translocation and docking. We also combine this high-resolution imaging approach with molecular biological tools to elucidate the molecular mechanisms controlling vesicle availability for release.

Regulation of neurotransmitter release and synaptic vesicle recycling

Current Projects

Short-term plasticity (STP) is widely believed to serve as one of the key neuronal mechanisms of information analysis. Despite several decades of intensive research, the synaptic mechanisms of STP are incompletely understood and the specific computations STP performs in the brain remain a subject of ongoing debate. To better understand the mechanisms and function of STP, we have developed a mechanistic model of STP, derived in a large part from basic principles of synaptic function. The model accurately reproduces all major   characteristics of synaptic dynamics during natural brain activity without free parameters (Kandaswamy et al, 2010). We then used the model to predict contributions of fundamental synaptic processes to neuronal computations and were able to  verify them experimentally. As an extension of this project we developed an information theory framework based on this STP model to be able to quantify synaptic information transmission. This analysis revealed unexpected  role of STP in optimizing information transmission for specific patterns of neuronal activity that may represent a   general principle governing neuronal communication in the brain (Rotman et al, 2011, 2013). We are now working to extend these findings to understand how converging neural signals influence information transmission in basic neural networks. 

Mechanisms and function of short-term synaptic plasticity 

The clinical symptoms of many neurological disorders, including Fragile X syndrome (FXS) arise in a large part from dysfunctions in communication between neurons in the brain. FXS is the most common form of inherited  mental retardation and the leading genetic cause  of autism. Despite two decades of intensive studies, the  causes of cognitive impairments in FXS remain incompletely understood. Our recent studies indicate that  dysregulation  of short-term forms of synaptic plasticity may play a significant role in the cognitive impairments in FXS (Deng et al, J Neurosci  2011). Our results revealed an unexpected novel mechanism of abnormal synaptic plasticity in Fragile X neurons that involves defects in voltage-gated ion channels the control action potential shape and duration (Deng et al, Neuron 2013). We are currently combining electrophysiology, molecular imaging with genetic and biochemical tools to rescue synaptic transmission and plasticity deficits in FXS mouse model and to define new targets for therapeutic intervention. We are also exploring several signaling pathways in synaptic terminals that we recently found to be abnormal in Fragile X neurons and defining their roles in synaptic, circuit and behavioral deficits in FXS. To this end we are combining molecular and cellular level studies with recordings in neural circuits and in vivo behavioral studies.     

 

 

Synaptic dysfunction in disease states