Opiate abuse potentiates the neuropathogenesis of HIV by synergistically increasing dendritic pathology (varicosity formation, beading, fragmentation, pruning), while promoting additive dendritic spine losses (plasticity). Behavioral deficits in spatial and non-spatial memory tasks are accompanied by synaptic losses and dendritic pathology preceding neuron death, suggesting that neuronal injury and reduced synaptic connectivity underlie the ability of opioids to aggravate HIV-associated neurological disorders (HAND). We have found that phenotypically distinct subpopulations of hippocampal CA1 interneurons appear to be highly sensitive to Tat ± opiates, and disruptions to these interneuron subpopulations may contribute, in part, to pyramidal cell dysfunction/injury. These findings represent a fundamental shift in our understanding of opioid drug action and propel the grant in novel directions. We hypothesize that opiates and HIV-induced hippocampal behavioral dysfunction is caused by disruptions to synaptic function and organization in vulnerable neuronal subpopulations that disrupt specific neural networks within the hippocampus. Aim 1 will characterize the neurophysiologic events underlying opioid and HIV-dependent neuronal dysfunction and injury in hippocampal CA1 pyramidal cells in whole-cell, patch-clamp recordings of CA1 pyramidal cells. Alterations in long-term potentiation and depression will be explored, as will deficits in subthreshold postsynaptic potentials in response to opiates and Tat. During patch-clamp recordings, neurons will be biocytin-filled and subsequently analyzed via 3D-reconstruction for dendritic pathology and spine density. Aim 2 will determine how vulnerable subsets of MOR-expressing CA1 interneurons exacerbate opiate and HIV-1-induced hippocampal dysfunction, neuronal injury, and disrupt network function. Tat tg mice will be crossed with MORfloxed;VGAT-Cre mice, which lack MOR+ CA1 interneurons. We will also determine how Tat and opiates affect synaptic processing and network function in CA1 by examining the integration of synaptic inputs by imaging genetically encoded-voltage indicators (GEVIs) selectively expressed in CA1 pyramidal neurons. Aim 3 will identify the neurophysiologic mechanisms underlying opiate and infectious HIV-1/HIV protein-induced neuronal dysfunction and injury in human hippocampal neurons. Opiate and Tat-induced neurophysiological and structural deficits will be correlated with deficits seen in Tat mice assessed in Aims 1 and 2. Our long-term goal is to define the mechanisms by which opiate drug abuse exacerbates neurodegenerative and functional defects, and to identify key underlying events that could be targeted therapeutically.