Mitogen-activated protein kinase phosphatase-2 deletion modifies ventral tegmental area function and connectivity and alters reward processing. MKP-2 deletion alters VTA function and connectivity

Karolina Pytka, Neil Dawson, Kyoko Tossell, Mark A. Ungless, Robin Plevin, Ros R. Brett, Trevor J. Bushell

Research output: Contribution to journalArticle

Abstract

Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.
Original languageEnglish
Number of pages73
JournalEuropean Journal of Neuroscience
DOIs
Publication statusAccepted/In press - 17 Jan 2020

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Mitogen-Activated Protein Kinase Phosphatases
Protein Phosphatase 2
Ventral Tegmental Area
Mitogen-Activated Protein Kinase 1
Reward
Mitogen-Activated Protein Kinases
Brain Diseases
Glucose
Neuronal Plasticity
Excitatory Postsynaptic Potentials
Dopaminergic Neurons
Nucleus Accumbens
Brain
Amphetamine
Fetal Development
Sucrose
Immune System
Hippocampus

Keywords

  • mitogen-activated protein kinase phosphatase-2
  • local cerebral glucose utilization
  • spontaneous excitatory postsynaptic current
  • sucrose preference
  • amphetamine-induced hyperlocomotion

Cite this

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title = "Mitogen-activated protein kinase phosphatase-2 deletion modifies ventral tegmental area function and connectivity and alters reward processing.: MKP-2 deletion alters VTA function and connectivity",
abstract = "Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.",
keywords = "mitogen-activated protein kinase phosphatase-2, local cerebral glucose utilization, spontaneous excitatory postsynaptic current, sucrose preference, amphetamine-induced hyperlocomotion",
author = "Karolina Pytka and Neil Dawson and Kyoko Tossell and Ungless, {Mark A.} and Robin Plevin and Brett, {Ros R.} and Bushell, {Trevor J.}",
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T1 - Mitogen-activated protein kinase phosphatase-2 deletion modifies ventral tegmental area function and connectivity and alters reward processing.

T2 - MKP-2 deletion alters VTA function and connectivity

AU - Pytka, Karolina

AU - Dawson, Neil

AU - Tossell, Kyoko

AU - Ungless, Mark A.

AU - Plevin, Robin

AU - Brett, Ros R.

AU - Bushell, Trevor J.

PY - 2020/1/17

Y1 - 2020/1/17

N2 - Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.

AB - Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.

KW - mitogen-activated protein kinase phosphatase-2

KW - local cerebral glucose utilization

KW - spontaneous excitatory postsynaptic current

KW - sucrose preference

KW - amphetamine-induced hyperlocomotion

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