Constitutive expression of HIV-1 viral proteins induces progressive synaptodendritic alterations in medium spiny neurons: implications for substance use disorders

Abstract Objectives Perinatally-infected adolescents living with HIV-1 (pALHIV) appear uniquely vulnerable to developing substance use disorders (SUD). Medium spiny neurons (MSNs) in the nucleus accumbens core (NAcc), an integrator of cortical and thalamic input, have been implicated as a key structural locus for the pathogenesis of SUD. To date, however, how constitutive expression of HIV-1 viral proteins alters the development of MSNs in the NAcc has not been systematically evaluated. Methods An innovative ballistic labeling technique was utilized to examine MSNs in the NAcc, and associated dendritic spines, in HIV-1 transgenic (Tg) and control animals. First, a time-sequential longitudinal experimental design was implemented, whereby animals were sacrificed at 30-day intervals from postnatal day (PD) 30 to PD 180. Second, the therapeutic efficacy of S-Equol for HIV-1-associated synaptic dysfunction in MSNs was evaluated using a cross-sectional experimental design. Results Constitutive expression of HIV-1 viral proteins disrupted the development of MSNs, evidenced by alterations in neuritogenesis and synaptogenesis. Furthermore, age-related, progressive synaptodendritic alterations were observed in the patterning of dendritic branches and dendritic spines, as well as dendritic spine head diameter, in HIV-1 Tg, relative to control, animals. Treatment with S-Equol during the formative period, however, led to long-term enhancements in synaptic function (i.e., PD 180). Conclusions Developmental and progressive synaptodendritic alterations in MSNs induced by chronic HIV-1 viral protein exposure may underlie the increased propensity for pALHIV to develop SUD. Elucidating a potential neural mechanism underlying the unique vulnerability of pALHIV to SUD affords a fundamental opportunity for the evaluation of therapeutics.