Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

R.L. Openshaw, D.M. Thomson, J.M. Penninger, J.A. Pratt, B.J. Morris

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Rationale Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear.

Objective In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment.

Methods Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT).

Results Once stable performance had been achieved, Map2k7+/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected.

Conclusions Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

LanguageEnglish
Pages293-305
Number of pages13
JournalPsychopharmacology
Volume234
Issue number2
Early online date24 Oct 2016
DOIs
Publication statusPublished - 31 Jan 2017

Fingerprint

Minocycline
Schizophrenia
Neocortex
Mitogen-Activated Protein Kinase Kinases
Tetracycline
Cognition
Genes
Reaction Time
Psychiatry
Phosphotransferases
Anti-Bacterial Agents
Cognitive Dysfunction

Keywords

  • cognition
  • schizophrenia
  • genetic risk
  • attention
  • minocycline
  • kinases
  • MMK7
  • JNK
  • MAP
  • mitogen-activated protein
  • c-Jun N-terminal kinase
  • upstream kinase
  • cognitive impairment
  • cognitive dysfunction

Cite this

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title = "Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline",
abstract = "Rationale Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results Once stable performance had been achieved, Map2k7+/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected. Conclusions Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.",
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AU - Openshaw, R.L.

AU - Thomson, D.M.

AU - Penninger, J.M.

AU - Pratt, J.A.

AU - Morris, B.J.

PY - 2017/1/31

Y1 - 2017/1/31

N2 - Rationale Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results Once stable performance had been achieved, Map2k7+/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected. Conclusions Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

AB - Rationale Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results Once stable performance had been achieved, Map2k7+/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected. Conclusions Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

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