Levetiracetam prevents neurophysiological changes and preserves cognitive function in the HIV-1 TAT transgenic mouse model of HIV-associated neurocognitive disorder.

Abstract

HIV-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV-protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the CNS and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here, we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and a shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice, but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. Significance Statement Around half of people living with HIV also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein TAT causes toxicity that is thought to contribute to HAND. Here, we show that an antiepileptic drug, levetiracetam (LEV), prevented synaptic and cognitive impairments that develop in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-treatment for neuroprotection in HAND.