Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Abstract

HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient's quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

Keywords: Cognitive impairment; Dendritic spines; Drug abuse; HAND; Neuroinflammation; Neuronal connectivity.

Fig. 1

Dendritic spine loss in HAND models can be reversed by different approaches. Recent studies have reported possible approaches to reverse dendritic spine deficits in animal models of HAND, which also improved their cognitive function. These approaches involved inhibiting excess Ca²⁺ influx into neurons (left panel) and promoting neuronal actin stabilization (right panel). In the left panel, HIV neurotoxin activation of Src causes excessive Ca²⁺ influx through NR2B-containing NMDA receptors (NMDAR) in the retrosplenial cortex, but inhibiting these receptors prevents excessive Ca²⁺ influx and spine retraction in the same region. In the right panel, CXCL12 binding to CXCR4 on cortical neurons activates a Rac1-mediated pathway that stabilizes actin, a critical structural component of dendritic spines, which protects existing spines. Interestingly, CXCL12 is also able to downregulate NR2B-containing NMDARs. Moreover, various estrogen and phytoestrogen molecules can increase dendritic spine density via estrogen receptor (ERα/β) signaling, which may also involve actin stabilization via Rac1 signaling. The mechanisms presented in this figure are explained in detail in the next section

Fig. 2

Mechanisms underlying synaptic scaling in hippocampal neurons. Synaptic scaling can serve as a feedback mechanism to prevent excitotoxicity by scaling down excitatory synapses (left panel) and increasing inhibitory synapses and transmission (right panel). Initially, HIV tat may increase NMDA receptor (NMDAR) activity by either directly interacting with the receptor or by promoting phosphorylation or membrane trafficking of intracellular NMDA receptors. Ion flux through NMDA receptors then activates the serine–threonine kinase Akt, which phosphorylates the E3 ubiquitin (Ub) ligase Mdm2. Mdm2 then ubiquitinates PSD95, an important structural component of dendritic spines, which promotes PSD95 degradation and corresponding de-potentiation of the synapse. Increased inhibition is mediated by both the initial ion influx via NMDA receptors and by gp120-mediated secretion of IL-1β from glial cells. First, IL-1β binds to neuronal IL-1 receptors (IL1R), which activates a P38-mediated pathway that leads to membrane insertion of α5-containing GABAa receptors (GABAaR) and enhanced inhibitory transmission. Additionally, IL1 receptor and NMDA receptor signaling activate the non-receptor tyrosine kinase Src, which at a later point leads to the synthesis of gephyrin, an important structural component of inhibitory synapses, its translocation to the membrane, and an increased number of inhibitory synapses

Fig. 3

Opioid and inflammatory regulation of ferritin heavy chain and corresponding effects on CXCR4 signaling and dendritic spines. Our studies indicate that µ-opioid agonists and inflammatory signaling pathways in cortical neurons converge to upregulate ferritin heavy chain (FHC), an iron storage protein that also inhibits CXCR4 signaling and produces corresponding dendritic spine deficits. Morphine activation of µ-opioid receptors (µOR) promotes de-acidification of endolysosomes and release of endolysosomal iron. This increases free labile iron in the cytosol, to which neurons respond by post-transcriptionally upregulating FHC protein levels. In the same system, FHC is also upregulated by inflammatory signaling pathways, including downstream of IL-1β/IL1 receptor (IL1R) and TNFα/TNF receptor (TNFR) signaling. In each case, FHC inhibits activation of CXCR4 via its natural ligand CXCL12, which prevents CXCR4-induced stabilization of dendritic spines. Normally, CXCL12/CXCR4 signaling enhances dendritic spine density by increasing the amount of activated, GTP-bound Rac1, which promotes a cascading phosphorylation of PAK1, LIMK, and the actin severing protein cofilin. Phosphorylation of cofilin blocks its ability to break down synaptic actin, which stabilizes dendritic spines and also reverses spine deficits in HIV-transgenic rats