Stephen Rayport, MD, PhD

Research focus is on cellular mechanisms of synaptic function and drug action in brain circuits relevant to addiction and schizophrenia. Using conditional and intersectional strategies we have identified behavioral roles of dopamine neuron glutamate cotransmission, in modulation of salience learning and amphetamine responsiveness. Motivated by the discovery of the reduction in glutamate cotransmission following acute amphetamine, and the diminished amphetamine responsiveness of mice with reduced glutamate cotransmission, we sought to identify the most susceptible dopamine neuron connections. We have now mapped dopamine neuron synaptic connectivity across the striatum, revealing a synaptic landscape of fast dopamine, glutamate and GABA signaling, including a novel mode of dopamine neuron glutamate cotransmission engaging metabotropic glutamate receptors. Now, we are elaborating amphetamine effects on the synaptic map, in response to both acute and chronic amphetamine, and how this translates into altered patterns of striatal activity. In efforts to extrapolate the mapping approach to clinical application, we have developed a novel proximity based methodology for synaptic visualization in transgenic mice, which we have extended to non-transgenic tissue from non-human primates, with potential for further extension to post-mortem human striatal tissue. We have targeted glutaminase (Gls1) for studies of dopamine neuron glutamate transmission as well as more broadly to define glutamatergic circuits crucial in the pathogenesis of schizophrenia and addiction. We have found that Gls1-deficient mice exhibit phenotypes consistent with schizophrenia resilience. In complimentary studies, we have targeted glutamate dehydrogenase (Glud1), and shown that CNS-Glud1 knockout mice have deficits in schizophrenia symptom domains, as well as a hippocampal imaging phenotype of hyperactivity, increased glutamate content, and associated atrophy. We are dissecting the regional basis for the phenotype and testing the therapeutic potential of glutaminase inhibition for the treatment of schizophrenia.

Significant contributions include:

1. Eestablishing the first postnatal cell cultures of identified dopamine neurons.
2. Elucidating a vesicular mechanism of amphetamine action.
3. Identifying glutamate as a fast dopamine neuron transmitter.
4. Generation and characterization of Gls1-deficient mice.
5. Characterizing the schizophrenia resilience phenotype of Gls1-heterozygous mice.
6. Showing that the phenotype is based significantly on reduction of dopamine neuron glutamate synaptic transmission.
7. Characterizing the schizophrenia phenotype of glutamate dehydrogenase (Glud1) deficient mice.
8. Developing genetic pharmacotherapy as a drug-development strategy for validating the potential of drug targets in advance of the development of drugs.
9. Mapping dopamine neuron synaptic transmission across the striatum.