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Sci Rep. 2016 Nov 7;6:36489. doi: 10.1038/srep36489.

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.

Author information

1
Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
2
Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
3
Laboratory for Molecular Neurobiology, VIB center for the biology of disease, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
4
Departement of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 7-9, 1005 Lausanne, Switzerland.

Abstract

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration.

PMID:
27819338
PMCID:
PMC5098239
DOI:
10.1038/srep36489
[Indexed for MEDLINE]
Free PMC Article

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