Jonathan Javitch, MD, PhD, Chief

Research in the newly created Division of Molecular Therapeutics focuses on understanding molecular and cellular processes that underlie behavior, with an emphasis on existing or novel targets for therapeutic intervention in psychiatric disorders. The Division has a specialized expertise in dopaminergic signaling, which involves midbrain dopamine neurons that project from the ventral tegmental area in the midbrain to the nucleus accumbens. These neurons are well known to mediate the rewarding effects of abused drugs, as well as to figure importantly in the pathogenesis of schizophrenia. There are four principal investigators in the division. Projects are multidisciplinary and range from studies on the biochemical and biophysical characterization of basic molecular processes that underlie drug responses, to cellular physiology, and to behavior.

The Rayport laboratory has shown that these neurons use glutamate as a co-transmitter and release glutamate from a subset of their synapses. The lab now uses transgenic mice with fluorescent dopamine neurons to explore the dynamic interaction between dopamine and glutamate release. They have also created transgenic mice with impaired glutamatergic transmission to address the role of glutamatergic cotransmission.

The Sulzer laboratory studies dopamine neuron synapses as the substrate for the action of drugs of abuse, including cocaine, amphetamine, nicotine, and opiates, and the role of these synapses in schizophrenic psychosis.  The lab studies the plasticity of neurotransmitter release in cortical, basal ganglia, and dopamine neurons in normal functions involved in learning, as well as events involved in dopamine neuron cell death, focusing on the substantia nigra dopamine neurons that are lost in Parkinson's disease, as well as the pathological basis of Huntington's disease and autism.

The Kellendonk laboratory’s research is directed at understanding the molecular mechanisms that may underlie the cognitive deficits of schizophrenia.  Because schizophrenia has a strong developmental component he is studying how molecular and/or anatomical alterations during early brain development affect cognition in the adult organism.  To this end he is generating and analyzing genetically modified mice. In a first mouse model he is analyzing how developmental up-regulation of dopamine D2 receptors in the striatum selectively leads to cognitive deficits that can be measured in the adult animal.

Research in the Schmauss lab focuses on two questions: Are specific regulatory transcriptional responses associated with specific domains of cognitive control functions that are modulated by dopamine? What are the mechanisms that alter the post-transcriptional regulation of neurotransmitter gene expression in response to stress and antipsychotic treatment? These studies are performed on different strains of wild-type mice as well as several knockout mice lacking individual dopamine receptors. The studies include behavioral assessments, quantitative stereological assessments of gene activation, and molecular studies of gene expression.

Research in the Javitch laboratory is aimed at understanding the structure, function and regulation of G protein-coupled receptors and neurotransmitter transporters using biochemical and biophysical approaches. Genetically engineered flies and mice are also being used to translate our molecular studies to the behavioral level. Transgenic mouse models are being created to explore the impact of specific manipulations of D2 receptor signaling in the striatum on prefrontal cortical function. In addition, knock-in mice have been created to explore the role of dopamine transporter phosphorylation in the acute and chronic actions of the psychostimulant amphetamine.