Rights statement: This is the peer reviewed version of the following article: Pytka, K, Dawson, N, Tossell, K, et al. Mitogen‐activated protein kinase phosphatase‐2 deletion modifies ventral tegmental area function and connectivity and alters reward processing. Eur J Neurosci. 2020; 00: 1– 15. https://doi.org/10.1111/ejn.14688 which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1111/ejn.14688 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Mitogen-activated protein kinase phosphatase-2 deletion modifies ventral tegmental area function and connectivity and alters reward processing
AU - Pytka, Karolina
AU - Dawson, Neil
AU - Tossell, Kyoko
AU - Ungless, Mark A
AU - Plevin, Robin
AU - Brett, Ros R
AU - Bushell, Trevor J
N1 - This is the peer reviewed version of the following article: Pytka, K, Dawson, N, Tossell, K, et al. Mitogen‐activated protein kinase phosphatase‐2 deletion modifies ventral tegmental area function and connectivity and alters reward processing. Eur J Neurosci. 2020; 00: 1– 15. https://doi.org/10.1111/ejn.14688 which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1111/ejn.14688 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
PY - 2020/7/1
Y1 - 2020/7/1
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 - amphetamine‐induced hyperlocomotion
KW - local cerebral glucose utilization
KW - mitogen‐activated protein kinase phosphatase‐2
KW - spontaneous excitatory postsynaptic current
KW - sucrose preference
U2 - 10.1111/ejn.14688
DO - 10.1111/ejn.14688
M3 - Journal article
C2 - 31989721
VL - 52
SP - 2838
EP - 2852
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
SN - 0953-816X
IS - 2
ER -