Information processing in the nervous system depends upon the electrical signal propagation along the neuron, and chemical and electrical signal propagation across neurons, referred to as synaptic transmission. Neurons constantly modify their molecular content to change their excitability and synaptic efficacy in order to process and store information in the network. Dysregulation of neuron excitability and synaptic efficacy is often manifested in neurological and psychiatric disorders, and thought to underlie some of the cognitive impairments and dysfunctions often seen in these diseases. Proteins are the key mediators of these processes and the prime targets for pharmacological interventions. Although the molecular components of these physiological phenomena were worked out in pioneering work, the precise function and molecular interplay is in most cases still elusive. With the combination of molecular manipulations in single neurons and a profound analysis of the electrophysiological properties, we want to dissect the molecular machinery in unprecedented precision.
Molecular mechanisms of NMDA receptor dependent synaptic plasticity
Activity-dependent changes in synaptic strength at glutamatergic synapses are considered to be the fundamental process in information processing and storage in the brain. This contributes directly to the development of neural circuit and experience-dependent behavioral plasticity including learning and memory. Many forms of plasticity existing in the brain can modify synaptic efficacy. One prominent model for activity-dependent synaptic plasticity is the NMDA receptor (NMDAR) dependent LTP and LTD (referred as LTP an LTD thereafter), which is mainly studied at hippocampal Schaffer collateral CA3-CA1 synapses. The hippocampus also plays a fundamental role in some forms of learning and memory, and has been implicated in a number of neurological and psychiatric disorders, including epilepsy, Alzheimer’s disease, and schizophrenia. Thus, understanding the mechanism underlying LTP and LTD may afford great insight in how synapses can be modified by experience. We will use lentivirus-mediated gene silencing and molecular replacement approaches to test how postsynaptic proteins regulate synaptic AMPAR function and how signaling specificity is achieved during the process of LTP and LTD.
The functional significance of L-type calcium channels in neurons
Neuronal L-type calcium channels (LTCCs) have been shown to be important in coupling membrane depolarization to a variety of neuronal processes including activity-dependent gene expression, mRNA stability, neuron excitability and synaptic plasticity. The dysregulation of LTCCs in hippocampus has been correlated with changes of neuronal intrinsic excitability, shifts of synaptic plasticity threshold, and hence, the cognitive impairment in aging and Alzheimer’s disease. In addition, in striatum and substantia niagra, the dysregulation of LTCCs is thought to contribute to the loss of neuronal connection in Parkinson’s disease. It is therefore important to understand how LTCCs regulate neuron activities under normal and diseased conditions. There are two types of neuronal LTCCs based upon the principal pore-forming subunits, CaV1.2- and CaV1.3-containing channels. They differ dramatically in their biophysical properties. However, little is known whether and how these two types of channels regulate neuron activity differently in hippocampus, largely because of the lack of specific blockers to either of these two channels for slice electrophysiology and their overlapping somatodendritic localization. Using molecular tools, we are going to address the specific functions of either of the channels.
Weifeng Xu majored in biophysics at Peking University. She received her PhD in neuroscience from Brown University. She completed her postdoctoral training in the Nancy Pritzker laboratory of Robert C. Malenka at the department of psychiatry and behavioral sciences at Stanford University Medical Center. In January 2009, she joined the Department of Brain and Cognitive Sciences and the Picower Institute for Learning and Memory at MIT.
Xu W. PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr Opin Neurobiol. 2011 Apr;21(2):306-12
Bhattacharyya S, Biou V, Xu W, Schlüter O, Malenka RC. A critical role for PSD-95/AKAP interactions in endocytosis of synaptic AMPA receptors. Nat Neurosci. 2009 Feb;12(2):172-81
Steiner P, Higley MJ, Xu W, Czervionke BL, Malenka RC, Sabatini BL. Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. Neuron. 2008 Dec 10;60(5):788-802. Erratum in: Neuron. 2009 Jan 15;61(1):152.
Schlüter OM, Xu W, Malenka RC. Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron. 2006 Jul 6;51(1):99-111.
Xu W, Schlüter OM, Steiner P, Czervionke BL, Sabatini B, Malenka RC. Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD. Neuron. 2008 Jan 24;57(2):248-62.