title: Enduring cortical alterations after a single in-vivo treatment of HIV-1 Tat.
abstract: HIV-1 proteins, including the transactivator of transcription (Tat), are believed to be involved in HIV-associated neurocognitive disorders by disrupting Ca²⁺ homeostasis, which leads to progressive dysregulation, damage, or death of neurons in the brain. We have found previously that bath-applied Tat abnormally increased Ca²⁺ influx through overactivated, voltage-sensitive L-type Ca²⁺ channels in pyramidal neurons within the rat medial prefrontal cortex (mPFC). However, it is unknown whether the Tat-induced Ca²⁺ dysregulation was mediated by increased activity and/or the number of the L-channels. This study tested the hypothesis that transient/early exposure to Tat in vivo promoted enduring L-channel dysregulation in the mPFC without neuron loss. Accordingly, rats were administered a single intracerebroventricular injection of recombinant Tat (80 μg/20 μl; diluted by cerebrospinal fluids to pathophysiological concentrations) or vehicle. Rats were killed 14 days after injection for immunohistochemical assessments of the mPFC, motor cortex, caudate-putamen, and nucleus accumbens. Stereological estimates for positively stained cells indicated a significant increase in the number of cells expressing the pore-forming Ca(v)1.2-α1c subunit of L-channels in the mPFC compared with other regions in Tat-treated or vehicle-treated rat brains. Optical density measurements showed a Tat-induced increase in glial fibrillary acidic protein expression, indicating astrogliosis in the cortical regions. There was no significant loss of neurons in any brain region investigated. These findings indicate that transient Tat exposure in vivo induced enduring L-channel dysregulation and astrogliosis in the mPFC without neuron loss. Such maladaptations may contribute toward dysregulated Ca²⁺ homeostasis and neuropathology in the PFC in the early stages of HIV infection.
authors: Rush University Medical Center, Chicago, Illinois 60612, USA. wesley_n_wayman@rush.edu
authors: Wesley N
authors: WN
authors: Wayman
authors: Hemraj B
authors: HB
authors: Dodiya
authors: Amanda L
authors: AL
authors: Persons
authors: Fatah
authors: F
authors: Kashanchi
authors: Jeffrey H
authors: JH
authors: Kordower
authors: Xiu-Ti
authors: XT
authors: Hu
authors: T Celeste
authors: TC
authors: Napier
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015497:HIV-1; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D020746:Calcium Channels, L-Type; D054322:tat Gene Products, Human Immunodeficiency Virus