Acquired neuronal channelopathies in HIV-associated dementia

Benjamin Gelman, Vicki M. Soukup, Kimberly W. Schuenke, Michael J. Keherly, Charles Holzer, Frances J. Richey, Christopher J. Lahart

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 2+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Gα 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.

Original languageEnglish (US)
Pages (from-to)111-119
Number of pages9
JournalJournal of Neuroimmunology
Volume157
Issue number1-2 SPEC. ISS.
DOIs
StatePublished - Dec 2004

Fingerprint

Channelopathies
AIDS Dementia Complex
Dementia
HIV-1
GTP-Binding Proteins
Encephalitis
G-Protein-Coupled Receptors
Neuroglia
Chlorides
Brain
HIV
Glycine Receptors
Voltage-Gated Potassium Channels
Neurons
Purinergic P1 Receptors
GABA Receptors
Membranes
Serotonin Receptors
Dopamine Receptors
N-Methyl-D-Aspartate Receptors

Keywords

  • Afterhyperpolarization
  • AIDS
  • Autopsy
  • Calcium
  • Calmodulin
  • Channelopathy
  • Chloride
  • Dementia
  • G protein
  • HIV encephalitis
  • Ionotropic
  • Membrane potential
  • Metabotropic
  • Potassium
  • Sodium

ASJC Scopus subject areas

  • Immunology
  • Clinical Neurology
  • Immunology and Allergy
  • Neurology

Cite this

Gelman, B., Soukup, V. M., Schuenke, K. W., Keherly, M. J., Holzer, C., Richey, F. J., & Lahart, C. J. (2004). Acquired neuronal channelopathies in HIV-associated dementia. Journal of Neuroimmunology, 157(1-2 SPEC. ISS.), 111-119. https://doi.org/10.1016/j.jneuroim.2004.08.044

Acquired neuronal channelopathies in HIV-associated dementia. / Gelman, Benjamin; Soukup, Vicki M.; Schuenke, Kimberly W.; Keherly, Michael J.; Holzer, Charles; Richey, Frances J.; Lahart, Christopher J.

In: Journal of Neuroimmunology, Vol. 157, No. 1-2 SPEC. ISS., 12.2004, p. 111-119.

Research output: Contribution to journalArticle

Gelman, B, Soukup, VM, Schuenke, KW, Keherly, MJ, Holzer, C, Richey, FJ & Lahart, CJ 2004, 'Acquired neuronal channelopathies in HIV-associated dementia', Journal of Neuroimmunology, vol. 157, no. 1-2 SPEC. ISS., pp. 111-119. https://doi.org/10.1016/j.jneuroim.2004.08.044
Gelman B, Soukup VM, Schuenke KW, Keherly MJ, Holzer C, Richey FJ et al. Acquired neuronal channelopathies in HIV-associated dementia. Journal of Neuroimmunology. 2004 Dec;157(1-2 SPEC. ISS.):111-119. https://doi.org/10.1016/j.jneuroim.2004.08.044
Gelman, Benjamin ; Soukup, Vicki M. ; Schuenke, Kimberly W. ; Keherly, Michael J. ; Holzer, Charles ; Richey, Frances J. ; Lahart, Christopher J. / Acquired neuronal channelopathies in HIV-associated dementia. In: Journal of Neuroimmunology. 2004 ; Vol. 157, No. 1-2 SPEC. ISS. pp. 111-119.
@article{e1c31305b70640978a16f52145753799,
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 2+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Gα 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.",
keywords = "Afterhyperpolarization, AIDS, Autopsy, Calcium, Calmodulin, Channelopathy, Chloride, Dementia, G protein, HIV encephalitis, Ionotropic, Membrane potential, Metabotropic, Potassium, Sodium",
author = "Benjamin Gelman and Soukup, {Vicki M.} and Schuenke, {Kimberly W.} and Keherly, {Michael J.} and Charles Holzer and Richey, {Frances J.} and Lahart, {Christopher J.}",
year = "2004",
month = "12",
doi = "10.1016/j.jneuroim.2004.08.044",
language = "English (US)",
volume = "157",
pages = "111--119",
journal = "Journal of Neuroimmunology",
issn = "0165-5728",
publisher = "Elsevier",
number = "1-2 SPEC. ISS.",

}

TY - JOUR

T1 - Acquired neuronal channelopathies in HIV-associated dementia

AU - Gelman, Benjamin

AU - Soukup, Vicki M.

AU - Schuenke, Kimberly W.

AU - Keherly, Michael J.

AU - Holzer, Charles

AU - Richey, Frances J.

AU - Lahart, Christopher J.

PY - 2004/12

Y1 - 2004/12

N2 - 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 2+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Gα 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.

AB - 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 2+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Gα 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.

KW - Afterhyperpolarization

KW - AIDS

KW - Autopsy

KW - Calcium

KW - Calmodulin

KW - Channelopathy

KW - Chloride

KW - Dementia

KW - G protein

KW - HIV encephalitis

KW - Ionotropic

KW - Membrane potential

KW - Metabotropic

KW - Potassium

KW - Sodium

UR - http://www.scopus.com/inward/record.url?scp=9644262611&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9644262611&partnerID=8YFLogxK

U2 - 10.1016/j.jneuroim.2004.08.044

DO - 10.1016/j.jneuroim.2004.08.044

M3 - Article

VL - 157

SP - 111

EP - 119

JO - Journal of Neuroimmunology

JF - Journal of Neuroimmunology

SN - 0165-5728

IS - 1-2 SPEC. ISS.

ER -