I graduated from Cornell University in 1979 with a B.S. in Biology with a concentration in Neurobiology. From 1979-1981 I worked in the laboratory of Dr. Richard Robertson in the Department of Anatomy and Neurobiology at the University of California, Irvine. I performed my doctoral studies in the laboratory of Dr. David Prince in the Department of Neurology and Neurological Sciences at Stanford University, and received my Ph. D. in 1986. I was a Postdoctoral Fellow in the labs of Prof. Beat GÃ¤hwiler in Zurich, Switzerland, and Dr. Robert Wong, then at Columbia University. In 1990, I returned to the University of Zurich, Switzerland, as an Assistant Professor at the Brain Research Institute. I completed my Habilitation in 1993 and was promoted to Associate Professor. In January, 1998, I joined the Department of Physiology of the University of Maryland, Baltimore, School of Medicine, where I received tenure in 2002.
Synaptic plasticity: We are interested in how and when synapses change their strength during learning and memory formation (i.e. long-term potentiation and depression, or LTP and LTD). We use a combined electrophysiological and morphological approach, including focal photolysis of chemically caged glutamate to individual dendritic spines (Bagal et al., 2005). This technique has allowed us to make unique observations about the kinetics of LTP expression and to identify a change in the subunit composition of the glutamate receptors at the potentiated spine. We have also used glutamate photolysis to study the role of glutamatergic signaling in the process of synapse formation.
Experimental epilepsy: We have investigated the genesis of epilepsy as a consequence of head injury (McKinney et al., 1997; Dinocourt et al., 2011). We found that lesions lead to the massive sprouting of new axons by mature hippocampal pyramidal cells and that these new axons form an excessive number of excitatory synapses (see figure of a GFP transfected pyramidal cell axon after injury below). This axonal sprouting increases the connectivity of the hippocampus and accounts for the development of hyperexcitability in lesioned tissue. We used transgenic mice expressing mutated trkB receptors to investigate the role of neurotrophins in the initiation of axonal sprouting after injury (Dinocourt et al., 2006), with the aim of preventing the development of posttraumatic epilepsy. In addition, we have used focal release of caged glutamate to reveal that the terminal dendritic branches of the denervated CA1 cells become hyperexcitable after Schaffer collateral transection (Wei et al., 2001; Cai et al., 2004; Cai et al., 2007).
Central pain syndrome: Our observation that denervation results in changes in neuronal excitability inspired us to consider the whether this mechanism could contribute to the genesis of central pain syndromes after spinal cord injury. We have generated a rat model of this debilitating chronic pain disorder and have observed abnormal excitability in thalamic brain slices taken from these animals (Wang and Thompson, 2008). We are excited about recent findings that a specific antiepileptic drug reduces both thalamic hyperexcitability and altered pain perception in our model. We look forward to beginning a small clinical trial in the near future.
Depression: The biological basis of cognitive dysfunction in major depression remains unknown. Antidepressant medications alter monoamine concentrations, particularly serotonin, but it remains uncertain which downstream events are critical to their therapeutic effects. We have discovered that endogenous serotonin selectively potentiates some, but not all, excitatory synapses in CA1 pyramidal cells via activation of 5-HT1BRs. This potentiation is expressed postsynaptically by AMPA-type glutamate receptors and requires calmodulin-dependent protein kinase-mediated phosphorylation of GluA1 subunits. We also observed that long-term potentiation and serotonin-induced potentiation occlude each other because they share common expression mechanisms and that long-term consolidation of spatial learning is enhanced by a 5-HT1BR antagonist. Most importantly, we observed that serotonin-induced potentiation is quantitatively and qualitatively altered in the chronic unpredictable mild stress model of depression and is restored by chronic antidepressant treatment. We are currently trying to understand the mechanisms underlying these alterations and to understand how they are induced by chronic stress. The change in serotonin-mediated potentiation of synaptic excitation, and its recovery by antidepressants, implicates excitatory synapses as a locus of plasticity in depression and suggests novel targets at which to direct new antidepressant therapies.
Lab Techniques and Equipment:
Thompson, S.M., A.J. Kallarackal, M.D. Kvarta, A.M. Van Dyke, T.A. LeGates, X. Cai. An excitatory synapse hypothesis of depression. Trends in Neurosciences, 38: 279–294, 2015. PMCID: PMC4417609