Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

Alexey Shevelkin, Chantelle Terrillion, Bagrat N. Abazyan, Tymoteusz J. Kajstura, Yan Jouroukhin, Gay L. Rudow, Juan C Troncoso, David J Linden, Mikhail Pletnikov

Research output: Contribution to journalArticle

Abstract

In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000–5000 μm3) and an increased number of smaller somata PCs (volume: 750–1000 μm3) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either Rinput or parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.

Original languageEnglish (US)
Pages (from-to)144-153
Number of pages10
JournalNeurobiology of Disease
Volume103
DOIs
StatePublished - Jul 1 2017

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Social Behavior
Purkinje Cells
Schizophrenia
Cell Size
Carisoprodol
Cerebellum
Patch-Clamp Techniques
Autistic Disorder

Keywords

  • Autism
  • Cerebellum
  • DISC1
  • Purkinje cells
  • Schizophrenia

ASJC Scopus subject areas

  • Neurology

Cite this

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title = "Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice",
abstract = "In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000–5000 μm3) and an increased number of smaller somata PCs (volume: 750–1000 μm3) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either Rinput or parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.",
keywords = "Autism, Cerebellum, DISC1, Purkinje cells, Schizophrenia",
author = "Alexey Shevelkin and Chantelle Terrillion and Abazyan, {Bagrat N.} and Kajstura, {Tymoteusz J.} and Yan Jouroukhin and Rudow, {Gay L.} and Troncoso, {Juan C} and Linden, {David J} and Mikhail Pletnikov",
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doi = "10.1016/j.nbd.2017.04.008",
language = "English (US)",
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T1 - Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

AU - Shevelkin, Alexey

AU - Terrillion, Chantelle

AU - Abazyan, Bagrat N.

AU - Kajstura, Tymoteusz J.

AU - Jouroukhin, Yan

AU - Rudow, Gay L.

AU - Troncoso, Juan C

AU - Linden, David J

AU - Pletnikov, Mikhail

PY - 2017/7/1

Y1 - 2017/7/1

N2 - In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000–5000 μm3) and an increased number of smaller somata PCs (volume: 750–1000 μm3) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either Rinput or parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.

AB - In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000–5000 μm3) and an increased number of smaller somata PCs (volume: 750–1000 μm3) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either Rinput or parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.

KW - Autism

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