J. Sutcliffe, PhD

Molecular Neurobiology. Our laboratory uses genomics-based tools to identify brain-specific proteins and to elucidate their functions. We recently described the hypocretins, two neuroexcitatory peptides expressed in a few thousand neurons of the dorsolateral hypothalamus. The hypocretins modulate the waking state and suppress rapid eye movement (REM) sleep. Disruption of the hypocretin signaling circuitry results in the sleep disorder narcolepsy. In collaboration with Digital Gene Technologies, Inc., we developed an automated, high throughput cDNA display technology called TOGA. We used this technology to study the mechanism of action of antipsychotic medications. Chronic administration of clozapine to rodents causes a significant increase in the accumulation of apolipoprotein D (apoD) in subsets of neurons and glia within the brain. In post-mortem samples of schizophrenic and bipolar subjects, apoD concentrations were significantly elevated over control levels in regions of pathophysiology. There is anatomical overlap in schizophrenia and bipolar disorder, as well as areas that distinguish the disorders. These data suggest a focal compensation that antipsychotic drug regimens augment. The hypothesis that schizophrenia and related illnesses are disorders of lipid metabolism provides an explanation for the diversity of symptoms associated with psychiatric disorders, and a means by which a number of different genetically, or otherwise, determined biochemical deficits could result in behavioral abnormalities. We are using mice carrying knockout mutations in neural genes to elucidate aspects of their functions, including the role of the postsynaptic, calmodulin-binding protein kinase C substrate RC3/neurogranin in postsynaptic neuroplasticity, and the role of the serotonin 5-HT7 receptor in circadian rhythms and thermoregulation.