Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.
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.
Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
Amira
A
Latif-Hernandez
Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
Disha
D
Shah
Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
Tariq
T
Ahmed
Laboratory for Molecular Neurobiology, VIB center for the biology of disease, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.|Departement of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 7-9, 1005 Lausanne, Switzerland.
Adrian C
AC
Lo
Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
Zsuzsanna
Z
Callaerts-Vegh
Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
Annemie
A
Van der Linden
Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
Detlef
D
Balschun
Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
Rudi
R
D'Hooge
D000818:Animals; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D008279:Magnetic Resonance Imaging / Q000379:methods; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects*
D016194:Receptors, N-Methyl-D-Aspartate; D017378:Quinolinic Acid