My principal research interest is synaptic transmission in the CNS, including both its normal regulation and its alteration under pathological conditions, such as epilepsy and chronic pain. We study excitatory and inhibitory synaptic responses in the hippocampus, a brain region that is important in memory and human epilepsy, using electrophysiological, fluorescent imaging, and cell biological techniques. Our studies are performed using brain slices, prepared either acutely or as organotypic slice cultures. My group has studied synaptic transmission and its regulation at the levels of single synapses, cell pairs, and synaptic networks. The projects encompass three themes:

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 are currently using 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 are also using glutamate photolysis to study the role of glutamatergic signaling in the process of synapse formation and the initiation of mRNA translation in dendrites.

Experimental epilepsy: We have also investigated the genesis of epilepsy as a consequence of head injury (McKinney et al., 1997). 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 are currently using 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). These projects are supported by an R01 grant from the National Institute of Neurological Disorders and Stroke.

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. 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. These projects are supported by an R21 grant from the National Institute of Neurological Disorders and Stroke.

Serotonin, stress, and depression: Serotonin signaling is a primary target of antidepressant medication, leading to the widespread hypothesis that serotonergic function is dysregulated in depression. This serotonin hypothesis of depression has been with us for decades, yet we still have essentially no idea what serotonin does to cells or synapses in brain regions involved in higher cognitive function, and no idea how the responses to serotonin that have been described might impact on cognitive function. Furthermore, we have no idea what key aspect of serotonergic function is disturbed in depression and no idea how that disturbance might cause the affective and cognitive problems that form the clinical signs of depression. We have recently discovered that serotonin acts to potentiate excitatory synapses selectively at TA-CA1 synapses, but not at Schaffer collateral synapses. The molecular basis of this mechanism was shown to be a postsynaptic, CaMK-mediated phosphorylation of GluR1 receptors at serine 831. We show further this process overlaps extensively with conventional LTP. W also discovered evidence to support an unexpected and precise hypothesis about the nature of the cognitive dysfunction in depression. We found that the actions of serotonin were qualitatively and quantitatively altered in a well accepted rat model of depression. Furthermore, we show that chronically administered antidepressants exert the exact opposite effect: an elimination of the potentiating action of serotonin. These two complimentary results suggest strongly that dysfunction of the normal regulation of the strength of excitatory synapses by serotonin is a key molecular mechanism underlying depression. Papers describing these results are under review at present.