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bioRxiv · 10.1101/2023.01.12.523788

Persistent Extrasynaptic Hyperdopaminergia in the mouse Hippocampus Induces Plasticity and Recognition Memory Deficits Reversed by Antipsychotics

Rocchetti, J.·Fasano, C.·Dal-Bo, G.·Guma, E.·El Mestikawy, S.·Wong, T. P.·Fakhfouri, G.·GIROS, B.
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Abstract

Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.

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Rocchetti, J., Fasano, C., Dal-Bo, G., Guma, E., El Mestikawy, S., Wong, T. P., Fakhfouri, G., GIROS, B.. 2023-01-13. Persistent Extrasynaptic Hyperdopaminergia in the mouse Hippocampus Induces Plasticity and Recognition Memory Deficits Reversed by Antipsychotics. https://doi.org/10.1101/2023.01.12.523788

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