Alterations in dendritic morphology such as dendritic pruning and synapse loss precede cell death in many neurodegenerative disorders, including HIV-1 associated dementia (HAD). Cognitive decline in patients with HAD is closely correlated with loss of excitatory synaptic connections. Loss of excitatory synapses following exposure to proteins released by HIV-1-infected cells occurs prior to and via a mechanism distinct from that leading to cell death. Synapse loss is reversible. Thus, loss of excitatory synapses appears to be a mechanism to cope with excess excitatory input induced by HIV-1 proteins. Neuronal networks, however, are comprised of both excitatory and inhibitory synaptic connections, and the dynamic interaction between the two defines the overall excitability of the network. The relative influence of inhibitory synapses in contributing to cognitive decline in HAD remains unclear. The premise of this proposal is that a better understanding of how inhibitory synaptic connections change when neural networks are exposed to HIV-1 proteins will ultimately improve how we understand and treat HAD. The focus of this study is the inhibitory post-synaptic density and how inhibitory synaptic connections change following exposure to HIV-1 proteins. Preliminary studies demonstrated that inhibitory synapse numbers increase when neuronal cultures are exposed to HIV-1 proteins as opposed to the marked decrease of excitatory synapses, suggesting that inhibitory synapses may scale to counteract HIV-1- induced increases in network excitability. The goal of the proposed research is to build on this foundation by to determine factors that modulate HIV-1 protein-induced changes in inhibitory synapses, mechanisms underlying the restoration of inhibitory synapses following exposure to HIV-1 proteins, and the possible role of cannabinoids in modulating these changes. Effort will be centered on three inter-related Specific Aims: (1) Determine the relationship between HIV-1 neurotoxin-induced alterations in excitatory and inhibitory synaptic connections. The hypothesis that inhibitory synaptic connections increase to compensate for network over- excitation induced by exposure to HIV-1 proteins will be tested. (2) Examine the ability of inhibitory synapses to return to basal levels following exposure to HIV-1 proteins. The hypothesis that stimuli known to induce recovery of excitatory synapses following HIV-1-induced loss will restore inhibitory synapses back to basal levels will be tested. (3) Investigate the effects of cannabinoids on HIV-1 protein-induced alterations in inhibitory synapses. The hypothesis that activation of cannabinoid receptors will protect from HIV-1 protein- induced increases in inhibitory synapses will be tested.
These specific aims will be carried out using live-cell confocal imaging to count postsynaptic densities, presynaptic syGCaMP2 imaging to assess network excitability, and pharmacology to determine the mechanism responsible. The insights gleaned from these studies will enhance our understanding of how inhibitory synapses respond to exposure to HIV-1 proteins, while offering new insights into possible pharmacotherapies targeting inhibitory synapses to treat HAD.
Cognitive decline in patients suffering from many neurodegenerative disorders, including HIV-1 associated dementia (HAD), is initially marked by loss of excitatory connections between neurons in many regions of the brain. The loss of these connections contributes to a network imbalance between excitatory and inhibitory connections and may contribute to aberrant network function. The proposed research examining changes in inhibitory connections as a result of HIV-1 infection and how these changes are modulated by cannabinoids will shed new light on the interaction between excitatory and inhibitory connections following exposure to HIV-1 proteins. These findings will provide insight into both the processes that underlie cognitive decline in HAD and the therapeutic potential of cannabinoids in the treatment of HAD.
| Berke, Brett; Wittnam, Jessica; McNeill, Elizabeth et al. (2013) Retrograde BMP signaling at the synapse: a permissive signal for synapse maturation and activity-dependent plasticity. J Neurosci 33:17937-50 |
| Hargus, Nicholas J; Thayer, Stanley A (2013) Human immunodeficiency virus-1 Tat protein increases the number of inhibitory synapses between hippocampal neurons in culture. J Neurosci 33:17908-20 |
