Prefrontal dopaminergic and enkephalinergic synaptic accommodation in HIV-associated neurocognitive disorders and encephalitis

Abstract

Changes in synapse structure occur in frontal neocortex with HIV encephalitis (HIVE) and may contribute to HIV-associated neurocognitive disorders (HAND). A postmortem survey was conducted to determine if mRNAs involved in synaptic transmission are perturbed in dorsolateral prefrontal cortex (DLPFC) in subjects with HIVE or HAND. Expression of the opioid neurotransmitter preproenkephalin mRNA (PENK) was significantly decreased in a sampling of 446 brain specimens from HIV-1 infected people compared to 67 HIV negative subjects. Decreased DLPFC PENK was most evident in subjects with HIVE and/or increased expression of interferon regulatory factor 1 mRNA (IRF1). Type 2 dopamine receptor mRNA (DRD2L) was decreased significantly, but not in the same set of subjects with PENK dysregulation. DRD2L downregulation occurred primarily in the subjects without HIVE or neurocognitive impairment. Subjects with neurocognitive impairment often failed to significantly downregulate DRD2L and had abnormally high IRF1 expression.

Conclusion: Dysregulation of synaptic preproenkephalin and DRD2L in frontal neocortex can occur with and without neurocognitive impairment in HIV-infected people. Downregulation of DRD2L in the prefrontal cortex was associated with more favorable neuropsychological and neuropathological outcomes; the failure to downregulate DRD2L was significantly less favorable. PENK downregulation was related neuropathologically to HIVE, but was not related to neuropsychological outcome independently. Emulating endogenous synaptic plasticity pharmacodynamically could enhance synaptic accommodation and improve neuropsychological and neuropathological outcomes in HIV/AIDS.

Fig. 1

Preproenkephalin (PENK), dopamine receptor (DRD2L), and interferon response factor 1 (IRF1) mRNAs in frontal neocortex in 67 seronegative patients and 446 patients with HIV/AIDS (Panels a, d, g). “Rel. expr.” on the ordinate denotes mRNA expression relative to GAPDH mRNA. The 446 subjects with HIV/AIDS were subdivided into groups without and with HIV encephalitis (HIVE) (n = 354 and 92 respectively). Panels b, c, e, f, h, i show the composite data split into subjects who died before (n = 111 and 23) and during (n = 243 and 69) the era of highly active antiretroviral therapy (HAART). The between group analysis using one-way analysis of variance was significant for PENK (F = 3.45, p < 0.0335), DRD2L (F = 7.78, p < 0.0005), and IRF1 (F = 7.03, p < 0.0010). PENK was lower in the subjects with HIVE (p < 0.0252); DRD2L was lower in the subjects without HIVE (p < 0.0021); IRF1 was higher with and without HIVE (p < 0.0007 and 0.0060 respectively). The patterns were present prior to and during the era of HAART. Mean ± standard deviation

Fig. 2

Changes in preproenkephalin (PENK) and dopamine receptor (DRD2L) mRNA expression in frontal neocortex in 446 HIV-infected subjects. PENK and DRD2L tended to run opposite to each other; the correlation coefficient was significant with a negative slope (a). When compared to the inflammatory marker IRF1 mRNA, PENK and DRD2L both were significantly correlated. PENK was correlated with a negative slope (b); DRD2L was correlated with a positive slope (c). Using the bootstrap approach, the correlations in b and c are significantly different from each other (p < 0.001)

Fig. 3

Preproenkephalin (PENK), dopamine receptor (DRD2L), and interferon response factor 1 (IRF1) mRNAs in frontal neocortex (a, b and c respectively). “Rel. expr.” on the ordinate denotes mRNA expression relative to GAPDH mRNA. On the abscissa 67 HIV negative subjects (HIV-) are compared to 146 HIV positive subjects (HIV+) with neurocognitive impairment (NPI), and 57 HIV+ subjects without NPI. The between group differences using one-way ANOVA were significant for DRD2L (F = 5.13, p < 0.0065) and IRF1 (F = 6.38, p < 0.0020). DRD2L was significantly lower in subjects without NPI (p < 0.0043, Tukey’s test). Mean ± standard deviation

Fig. 4

Preproenkephalin mRNA concentration (PENK) in frontal neocortex of HIV-infected subjects is plotted versus substance abuse categories. “Rel. expr.” on the ordinate denotes mRNA expression relative to GAPDH mRNA. Drug abuse was diagnosed using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM). Drug abuse categories are given on the abscissa. “Other” denotes several substances such as inhalants. See “Results” for the number of subjects in each category. PENK was not significantly different in any substance abuse category using multiple regression models. Compared to subjects without any abuse (left bar), eleven subjects with opiate abuse had a trend towards having significantly less PENK using stepwise regression models that was of marginal significance (see “Results”). DRD2L mRNA also showed no significant group effect (not illustrated). Mean ± standard deviation

Fig. 5

Prefrontal dopamine receptive neurons in HIV infected subjects often have abnormal mRNA expression of genes that are critical for synaptic transmission. The proposed functional implications for a dopaminergic synapse of a Lamina V pyramidal neuron are illustrated in four scenarios designated a, b, c and d. Scenario A depicts baseline dopaminergic tone in a normal person. Scenario B depicts no change in postsynaptic DRD2L; subjects fitting that picture were more likely to have neurocognitive impairment and high excitatory frontal lobe output. Scenario C depicts a decrease in postsynaptic DRD2L due to accommodation; subjects fitting that picture were less likely to have neurocognitive impairment and lower excitatory output. Scenario D depicts HIV encephalitis which produces an increase in inflammatory mediators; subjects fitting that picture probably had bidirectional changes in DRD2L, including increased expression when inflammation and HIVE were present. Inflammation and HIVE also were associated with decreased PENK expression, which ran opposite to DRD2L regulation. The nature of the suggested connection between dopaminergic and enkephalinergic transmission remains to be elucidated. Key: The presynaptic bouton is on top and postsynaptic bouton is below. For the purpose of illustration, the postulated driver of postsynaptic DRD2L expression is increased presynaptic dopaminergic tone (the cause is not clear). A larger size of the DRD2L symbol denotes higher receptor mRNA expression. Bolder arrows denote stronger receptor transduction. Bolder lightning bolts denote stronger depolarization or high firing rates. A high density of presynaptic vesicles symbolizes higher presynaptic tone