Understanding Brain Disease
Our laboratory has expanded its focus to include brain-disease related studies, including dementia, schizophrenia, and depression. In a series of studies we've examined the effects of A-beta on synapses. Aβ peptide, a preteolytic product of APP, is thought to be central to the pathogenesis of Alzheimer's disease; however, the functional relationship of APP and A-beta to neuronal conductance is mostly unexplored territory. Our laboratory has recently shown that neuronal activity modulates the formation and secretion of Aβ peptides from neurons. In turn, Aβ depresses synaptic transmission. Synaptic depression from excessive Aβ could contribute to cognitive decline during early Alzheimer's disease. In addition, activity-dependent modulation of Aβ production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in Alzheimer's disease. These studies shed new light on the role of Aβ in normal and diseased states, and may lead to new treatments of Alzheimer's disease.
In a project related to depressive disorders, we have found that a group of excitatory synapses in the lateral habenula are dramatically potentiated in rodent models of depression. The lateral habenula was shown to encode ‘disappointment’ signals in monkey studies. Thus, negative rewards are likely heightened while positive rewards are diminished. We seek to understand the nature of synaptic potentiation in this circuit and its relationship to mood disorders, and plan to utilize our arsenal of techniques to test if these hyperactive synapses are responsible for behavioral depression.