Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia

D. J. Holt; M. M. Herman; T. M. Hyde; J. E. Kleinman; C. M. Sinton; D. C. German; L. B. Hersh; A. M. Graybiel; C. B. Saper

doi:10.1016/S0306-4522(99)00279-1

Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia

D. J. Holt, M. M. Herman, T. M. Hyde, J. E. Kleinman, C. M. Sinton, D. C. German, L. B. Hersh, A. M. Graybiel, C. B. Saper

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Abstract

Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 ± 0.48 cells/mm² (mean ± S.D.), schizophrenics: 2.43 ± 0.68 cells/mm²; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 ± 0.59 cells/mm², schizophrenics: 2.52 ± 0.64 cells/mm²; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

Original language	English
Pages (from-to)	21-31
Number of pages	11
Journal	Neuroscience
Volume	94
Issue number	1
DOIs	https://doi.org/10.1016/S0306-4522(99)00279-1
State	Published - Sep 1999

Bibliographical note

Funding Information:
We are grateful to Minh Ha, Quan Hue Ha, Dr Juraj Cervenak, and Glenn Holm for excellent technical assistance, to the Maryland Psychiatric Institute and the McLean Brain Bank for contributions of schizophrenic cases, and to Drs Kari Steffansson and Addy Kendlar for contributions of control cases. We are indebted to Dr Marco Celio for donating a sheep anti-calretinin antibody and for the comparison of its staining with choline acetytransferase antiserum; and to Dr Shelley Hurwitz for performing the analysis of covariance on our data. This work was supported by grants from the Charles A. and Leila Y. Mathers Foundation, the Theodore and Vada Stanley Foundation, and USPHS National Research Service Award MH-10522 to DJH and Javits award NS25529 to AMG.

Keywords

Basal ganglia
Cholinergic
Human
Interneuron
Schizophrenia
Striatum

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0306-4522(99)00279-1

Cite this

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title = "Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia",

abstract = "Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 ± 0.48 cells/mm2 (mean ± S.D.), schizophrenics: 2.43 ± 0.68 cells/mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 ± 0.59 cells/mm2, schizophrenics: 2.52 ± 0.64 cells/mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.",

keywords = "Basal ganglia, Cholinergic, Human, Interneuron, Schizophrenia, Striatum",

author = "Holt, {D. J.} and Herman, {M. M.} and Hyde, {T. M.} and Kleinman, {J. E.} and Sinton, {C. M.} and German, {D. C.} and Hersh, {L. B.} and Graybiel, {A. M.} and Saper, {C. B.}",

note = "Funding Information: We are grateful to Minh Ha, Quan Hue Ha, Dr Juraj Cervenak, and Glenn Holm for excellent technical assistance, to the Maryland Psychiatric Institute and the McLean Brain Bank for contributions of schizophrenic cases, and to Drs Kari Steffansson and Addy Kendlar for contributions of control cases. We are indebted to Dr Marco Celio for donating a sheep anti-calretinin antibody and for the comparison of its staining with choline acetytransferase antiserum; and to Dr Shelley Hurwitz for performing the analysis of covariance on our data. This work was supported by grants from the Charles A. and Leila Y. Mathers Foundation, the Theodore and Vada Stanley Foundation, and USPHS National Research Service Award MH-10522 to DJH and Javits award NS25529 to AMG.",

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doi = "10.1016/S0306-4522(99)00279-1",

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AU - Holt, D. J.

AU - Herman, M. M.

AU - Hyde, T. M.

AU - Kleinman, J. E.

AU - Sinton, C. M.

AU - German, D. C.

AU - Hersh, L. B.

AU - Graybiel, A. M.

AU - Saper, C. B.

N1 - Funding Information: We are grateful to Minh Ha, Quan Hue Ha, Dr Juraj Cervenak, and Glenn Holm for excellent technical assistance, to the Maryland Psychiatric Institute and the McLean Brain Bank for contributions of schizophrenic cases, and to Drs Kari Steffansson and Addy Kendlar for contributions of control cases. We are indebted to Dr Marco Celio for donating a sheep anti-calretinin antibody and for the comparison of its staining with choline acetytransferase antiserum; and to Dr Shelley Hurwitz for performing the analysis of covariance on our data. This work was supported by grants from the Charles A. and Leila Y. Mathers Foundation, the Theodore and Vada Stanley Foundation, and USPHS National Research Service Award MH-10522 to DJH and Javits award NS25529 to AMG.

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N2 - Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 ± 0.48 cells/mm2 (mean ± S.D.), schizophrenics: 2.43 ± 0.68 cells/mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 ± 0.59 cells/mm2, schizophrenics: 2.52 ± 0.64 cells/mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

AB - Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 ± 0.48 cells/mm2 (mean ± S.D.), schizophrenics: 2.43 ± 0.68 cells/mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 ± 0.59 cells/mm2, schizophrenics: 2.52 ± 0.64 cells/mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

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Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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