Project Summary/Abstract: Psychotic symptoms (hallucinations and delusions) are highly prevalent Alzheimer's disease. Unfortunately, the antipsychotic medications used to treat psychosis are contraindicated in the elderly where the Food and Drug Administration (FDA) issued a black-box warning for all first- and second-generation antipsychotic medications indicating that these drugs increase the risk of death in elderly dementia patients. We have demonstrated that the hippocampus plays a central role in the regulation of dopamine system function and that aberrant hippocampal regulation of dopamine neuron activity likely contributes to psychosis in schizophrenia. Given that the hippocampus is a key site of pathology in AD, we posit that the hippocampus may be a site of convergence contributing to comorbid psychosis in AD, and we will use rodent models to study this hypothesis. Specifically, we will examine basal activity and afferent regulation of dopamine neuron activity as well as behavioral correlates of psychosis in two distinct rodent models of AD (Aim 1). We will then examine the consequence of AD pathology on vHipp interneuron function and whether transplantation of stem cell derived interneurons (Aim 2) or pharmacological modulation of hippocampal function (Aim 3) can reverse aberrant neuronal activity and behavior in AD models. This proposal with therefore identify a potential novel therapeutic target and inform the development of more effective treatment approaches for AD and comorbid psychosis.

Project Narrative: An often overlooked symptom associated with Alzheimer's disease (AD) is psychosis (hallucinations and delusions), which are reported in over 50% of AD patients. Unfortunately, the antipsychotic medications used to treat psychosis are contraindicated in the elderly where they increase the risk of death. Here we examine the mechanisms contributing to comorbid psychosis in AD and evaluate whether pharmacological manipulation of hippocampal GABAergic signaling may be a potentially novel therapeutic approach for the symptoms of AD and comorbid psychosis.