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Published on: March 23, 2011
HIV-Induced Hyperactivity of Striatal Neurons Is Associated with Dysfunction of Voltage-Gated Calcium and Potassium
Christina E Khodr1, Lihua Chen1, Lena Al-Harthi1
1Department of Microbial Pathogens and Immunity, Rush University Medical Center, Cohn Research Building, Rm.610, 1735 W. Harrison Street, Chicago, IL 60612, USA.
Insights
HIV-1 infection in aging rats causes striatal neuron dysfunction, with increased firing and reduced calcium spikes. This neuroHIV-associated change in medium spiny neurons is linked to altered L-channel forms.
Area of Science:
- Neuroscience
- Virology
- Aging Research
Background:
- HIV-associated neurocognitive disorders (HAND) affect about 50% of people living with HIV (PLWH) despite treatment.
- Corticostriatal pathway dysfunction is linked to HAND, but the underlying mechanisms in the striatum remain unclear.
- Aging may exacerbate neuroHIV, impacting neuronal function in critical brain regions.
Purpose of the Study:
- To investigate the functional activity and protein expression of striatal medium spiny neurons (MSNs) in aging HIV-1 transgenic (HIV-1 Tg) rats.
- To elucidate the specific alterations in neuronal excitability, calcium signaling, and ion channel function in the context of neuroHIV during aging.
- To explore the relationship between striatal MSN dysfunction and previously observed changes in the medial prefrontal cortex (mPFC) in neuroHIV.
Main Methods:
- Patch-clamp electrophysiology was used to assess the firing patterns, calcium (Ca2+) spikes, and potassium (K+) channel activity of MSNs in dorsal striatum slices.
- Western blotting or similar techniques were employed to quantify the protein expression levels of specific voltage-gated calcium channels (CaV1.2/CaV1.3), NMDA receptors (NR2B subunit), and GABA-A receptors (β2,3 subunit).
- Comparisons were made between 12-month-old HIV-1 Tg rats and age-matched non-transgenic (non-Tg) control rats.
Main Results:
- MSNs in 12-month-old HIV-1 Tg rats exhibited significantly increased firing rates compared to controls.
- A significant reduction in Ca2+ spike amplitude and frequency was observed in MSNs from HIV-1 Tg rats.
- Increased K+ channel activity and altered expression of a shorter, less functional CaV1.2 L-channel form were found in HIV-1 Tg rats, while NR2B and GABA-A receptor expression remained unchanged.
- These findings indicate a distinct pattern of MSN dysfunction in middle-aged neuroHIV rats compared to younger rats.
Conclusions:
- This study provides the first evidence of neuroHIV-induced striatal MSN dysfunction in middle-aged rats, characterized by altered firing and calcium dynamics.
- The observed MSN dysfunction is associated with changes in L-type calcium channel expression and is uncoupled from previously identified VGCC upregulation and reduced Kv activity in younger rats.
- The findings suggest a complex interplay between aging, HIV infection, and striatal neuronal function, potentially linked to prefrontal cortex alterations, warranting further investigation into receptor-mediated mechanisms.
Abstract:
Despite combination antiretroviral therapy, HIV-associated neurocognitive disorders (HAND) occur in ~50% of people living with HIV (PLWH), which are associated with dysfunction of the corticostriatal pathway. The mechanism by which HIV alters the neuronal activity in the striatum is unknown. The goal of this study is to reveal the dysfunction of striatal neurons in the context of neuroHIV during aging. Using patch-clamping electrophysiology, we evaluated the functional activity of medium spiny neurons (MSNs), including firing, Ca2+ spikes mediated by voltage-gated Ca2+ channels (VGCCs), and K+ channel-mediated membrane excitability, in brain slices containing the dorsal striatum (a.k.a. the caudate-putamen) from 12-month-old (12mo) HIV-1 transgenic (HIV-1 Tg) rats. We also assessed the protein expression of voltage-gated Cav1.2/Cav1.3 L-type Ca2+ channels (L-channels), NMDA receptors (NMDAR, NR2B subunit), and GABAA receptors (GABAARs, β2,3 subunit) in the striatum. We found that MSNs had significantly increased firing in 12mo HIV-1 Tg rats compared to age-matched non-Tg control rats. Unexpectedly, Ca2+ spikes were significantly reduced, while Kv channel activity was increased, in MSNs of HIV-1 Tg rats compared to non-Tg ones. The reduced Ca2+ spikes were associated with an abnormally increased expression of a shorter, less functional Cav1.2 L-channel form, while there was no significant change in the expression of NR2Bs or GABAARs. Collectively, the present study initially reveals neuroHIV-induced dysfunction of striatal MSNs in 12mo-old (middle) rats, which is uncoupled from VGCC upregulation and reduced Kv activity (that we previously identified in younger HIV-1 Tg rats). Notably, such striatal dysfunction is also associated with HIV-induced hyperactivity/neurotoxicity of glutamatergic pyramidal neurons in the medial prefrontal cortex (mPFC) that send excitatory input to the striatum (demonstrated in our previous studies). Whether such MSN dysfunction is mediated by alterations in the functional activity instead of the expression of NR2b/GABAAR (or other subtypes) requires further investigation.
