Synaptodendritic injury is thought to underlie HIV-associated neurocognitive disorders and contributes to exaggerated inflammation

Memory deficits are characteristic of HIV-associated neurocognitive disorders (HAND) and co-occur with hippocampal pathology. The HIV-1 transactivator of transcription (Tat), a regulatory protein, plays a significant role in these events, but the cellular mechanisms involved are poorly understood. Within the hippocampus, diverse populations of interneurons form complex networks; even subtle disruptions can drastically alter synaptic output, resulting in behavioral dysfunction. We hypothesized that HIV-1 Tat would impair cognitive behavior and injure specific hippocampal interneuron subtypes. Male transgenic mice that inducibly expressed HIV-1 Tat (or non-expressing controls) were assessed for cognitive behavior or had hippocampal CA1 subregions evaluated via interneuron subpopulation markers. Tat exposure decreased spatial memory in a Barnes maze and mnemonic performance in a novel object recognition test. Tat reduced the percentage of neurons expressing neuronal nitric oxide synthase (nNOS) without neuropeptide Y immunoreactivity in the stratum pyramidale and the stratum radiatum, parvalbumin in the stratum pyramidale, and somatostatin in the stratum oriens, which are consistent with reductions in interneuron-specific interneuron type 3 (IS3), bistratified, and oriens-lacunosum-moleculare interneurons, respectively. The findings reveal that an interconnected ensemble of CA1 nNOS-expressing interneurons, the IS3 cells, as well as subpopulations of parvalbumin- and somatostatin-expressing interneurons are preferentially vulnerable to HIV-1 Tat. Importantly, the susceptible interneurons form a microcircuit thought to be involved in feedback inhibition of CA1 pyramidal cells and gating of CA1 pyramidal cell inputs. The identification of vulnerable CA1 hippocampal interneurons may provide novel insight into the basic mechanisms underlying key functional and neurobehavioral deficits associated with HAND.

Despite marked regional differences in HIV susceptibility within the CNS, there has been surprisingly little exploration into the differential vulnerability among neuron types and the circuits they underlie. The dorsal striatum is especially susceptible, harboring high viral loads and displaying marked neuropathology, with motor impairment a frequent manifestation of chronic infection. However, little is known about the response of individual striatal neuron types to HIV or how this disrupts function. Therefore, we investigated the morphological and electrophysiological effects of HIV-1 trans-activator of transcription (Tat) in dopamine subtype 1 (D1) and dopamine subtype 2 (D2) receptor-expressing striatal medium spiny neurons (MSNs) by breeding transgenic Tat-expressing mice to Drd1a-tdTomato-or Drd2-eGFPreporter mice. An additional goal was to examine neuronal vulnerability early during the degenerative process to gain insight into key events underlying the neuropathogenesis. In D2 MSNs, exposure to HIV-1 Tat reduced dendritic spine density significantly, increased dendritic damage (characterized by swellings/varicosities), and dysregulated neuronal excitability (decreased firing at 200 -300 pA and increased firing rates at 450 pA), whereas insignificant morphologic and electrophysiological consequences were observed in Tat-exposed D1 MSNs. These changes were concomitant with an increased anxiety-like behavioral profile (lower latencies to enter a dark chamber in a light-dark transition task, a greater frequency of light-dark transitions, and reduced rearing time in an open field), whereas locomotor behavior was unaffected by 2 weeks of Tat induction. Our findings suggest that D2 MSNs and a specific subset of neural circuits within the dorsal striatum are preferentially vulnerable to HIV-1.

Highlights d Hippocampus and amygdala mediate experience-dependent observational fear (Exp OF) d Exp OF requires fear memory engram cells encoding prior similar fear experiences d The dorsal hippocampus generates memory engram cells in the basolateral amygdala (BLA) d The ventral hippocampus reactivates memory engram cells in BLA to facilitate Exp OF

Rectifying electrical synapses are rare gap junctions that favor transmission of signals in one direction. Such synapses have been identified in neural systems, including those mediating rapid escape responses of arthropods. In the Drosophila giant fiber system, adjacent cells express and contribute different transcript variants of the innexin Shaking B, resulting in heterotypic gap junctions with rectifying properties. When expressed exogenously, variants Shaking B Lethal (ShakBL) and Shaking B neural + 16 (ShakBN16) form heterotypic junctions that gate asymmetrically in response to transjunctional voltage. To determine whether the amino terminus confers properties of gating and rectification, amino-terminal domains were exchanged between ShakBL and ShakBN16, creating chimeric proteins SBL NTN16 and SBN16 NTL. The properties were analyzed in paired Xenopus oocytes. Our results suggest that the amino terminus plays an important role in establishing rectifying properties inherent to heterotypic junctions composed of ShakBL and ShakBN16. ShakBL/SBL NTN16 junctions behaved similarly to ShakBL/ShakBN16 junctions, gating in response to transjunctional voltage of one polarity and inducing a highly asymmetric conductance-voltage relationship. However, the amino terminus did not act independently to confer sensitivity to transjunctional voltage. The complementary pairing ShakBN16/SBN16 NTL displayed little sensitivity to voltage of either polarity, and in homotypic pairings SBL NTN16 was strongly gated by transjunctional voltage. We propose a model in which the amino terminus induces gating only when matched with an accommodating innexin body.