title: Acquired neuronal channelopathies in HIV-associated dementia.
abstract: A gene expression profile of the human brain cortex was performed in people with HIV-1-associated dementia (HAD) using Affymetrix HG-U133 chips. Messenger RNA transcripts in middle frontal gyrus from subjects with HAD or milder neurocognitive dysfunction were compared to HIV-negative people. The analysis focused on ionic conductance carriers that control membrane excitation. Overexpressed ionic channel genes in brain cortex of subjects with dementia included (1) a calcium-driven K+ channel that prolongs afterhyperpolarization (AHP) current, (2) a leak type of K+ channel that prolongs the AHP, (3) an adenosine receptor that modulates cationic current via G proteins, (4) a G protein-coupled serotonin receptor that modulates cyclic AMP-linked current transduction, (5) a G protein-coupled dopamine receptor, (6) a GABA receptor subunit that conducts chloride current. Underexpressed current generators in the demented subjects included (1) two voltage-gated K+ channels that influence refractory periods and the onset of AHP, (2) a Na+ channel subunit that modifies current inactivation and the onset of the AHP, (3) a neuronal type of voltage-sensitive Ca+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Galpha protein that transduces metabotropic cationic current, (6) an NMDA receptor subunit, (7) a glycine receptor subunit that modulates chloride current. These gene expression shifts probably occurred in neurons because they were not present in gyral white matter. Acquired neuronal channelopathies were not associated with a generalized shift of neuronal or glial cell markers, which suggest that they were not an artifact produced by neurodegeneration and/or glial cell proliferation. Channelopathies were not correlated with a generalized increase of inflammatory cell transcripts and were present in demented people without, and with HIV encephalitis (HIVE). We surveyed experimentally induced perturbations of these channels to determine the implications for brain function. Eleven experimental channelopathies produced decreased neuronal firing frequencies and pacemaker rates in model neurons; seven channelopathies increase neuronal firing rates experimentally. The implied disruption of neuronal excitability is consistent with some features of HAD, including its potential reversibility after HIV-1 replication is suppressed, the abnormal electroencephalographic recordings, the lack of clear-cut correlation with neurodegeneration and the lack of strict correlation with brain inflammation. The channelopathy concept may have wide relevance to the subcortical dementias.
authors.affiliation: Texas NeuroAIDS Research Center Department of Pathology, Rt 0785, University of Texas Medical Branch, Galveston, TX 77555-0785, USA. bgelman@utmb.edu
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: Vicki M
authors.initials: VM
authors.lastname: Soukup
authors.forename: Kimberly W
authors.initials: KW
authors.lastname: Schuenke
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keherly
authors.forename: Charles
authors.initials: C
authors.lastname: Holzer
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Richey
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lahart
mesh_terms: D015526:AIDS Dementia Complex / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007473:Ion Channels / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D012333:RNA, Messenger; D011956:Receptors, Cell Surface