Ewens, Ashley2024-04-302024-04-302024https://hdl.handle.net/11299/262862University of Minnesota Ph.D. dissertation. 2024. Major: Pharmacology. Advisor: Stanley Thayer. 1 computer file (PDF); 121 pages.Worldwide, 39 million people are currently HIV-positive; around half of these individuals also suffer from HIV-associated neurocognitive disorder (HAND). HAND symptoms range from subclinical cognitive impairment to HIV-associated dementia. Once people living with HIV (PLWH) have one form of HAND, they are at much higher risk of developing more severe types, which are correlated with worse prognosis and decreased survival. Currently, there is no treatment available specifically for HAND and its mechanism of manifestation has not been fully elucidated. Combined antiretroviral therapy (cART), the first line treatment for HIV, has greatly extended the lifespan of PLWH. However, cART has not improved the prevalence of HAND. This suggests that HIV can continue to cause damage even at virologically controlled levels. Indeed, the virus lies latent in microglial viral reservoirs and continues to produce HIV-associated proteins, several of which have been implicated in HAND. There is conclusive evidence that trans-activator of transcription (TAT) persists in the central nervous system despite cART and contributes to the development of HAND. TAT has a wide range of neurotoxic effects, the most damaging of which include magnifying inflammation, impairing the endocannabinoid system, over-activating NMDA receptors, and upregulating inhibitory signaling. In addition, TAT aids the HIV virus in attracting and entering uninfected immune cells, supporting its continued replication. Therefore, a treatment specifically against TAT’s neurotoxicity deserves more investigation. Overall, the modifications to the immune system, endocannabinoid system, NMDA receptors, and inhibitory signaling create an environment conducive to excitatory dysfunction. TAT has also been shown to directly manipulate glutamate signaling and cycling. As a result, TAT has been implicated in causing epileptic activity, although there is limited research. This is supported by the evidence that PLWH have seizures five times more than the general population. Additionally, epileptic activity has been demonstrated to be pathogenic in Alzheimer’s disease (AD), which bears many similarities to HAND pathology. Excitingly, not only could this activity be reversed in AD-model mice, but cognition was also preserved using an anti-epileptic drug, levetiracetam (LEV). Since PLWH are at risk for developing seizures that may worsen cognition, LEV could be used as a protective strategy against seizures and cognitive decline. Here, I show for the first time that LEV prevented synaptic and cognitive impairments that develop in a TAT-expressing mouse model. Inducible TAT (iTAT) transgenic male mice had an increased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) in hippocampal slice recordings. Furthermore, iTAT mice had impaired long-term potentiation (LTP), a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV through osmotic minipumps prevented both impairments. Additionally, kainic acid induced a higher maximum behavioral seizure score, longer seizure duration, and a shorter latency to first seizure, consistent with a lower seizure threshold in iTAT mice. Acute LEV administration reduced seizures in control and iTAT mice. Lastly, iTAT mice showed cognitive impairments in the Barnes maze that were prevented by chronic LEV administration. Thus, a TAT-induced increase in glutamatergic synaptic activity drives functional deficits in this model of HAND. LEV not only prevented aberrant synaptic activity in iTAT mice, but also restored cognitive function. LEV provides a pharmacological approach to prevent neurodegenerative processes and is a promising strategy to afford neuroprotection in HAND. This study supports further investigation of the use of LEV for clinical neuroprotection in HAND patients.enHIV-associated neurocognitive disorderHIV-TATLevetiracetamLTPmouse behaviorsEPSCThesis or Dissertation