Medial prefrontal cortex ablation results in impaired spatial memory and hippocampal long-term potentiation with increased functional connectivity in vivo

Abstract

Event Abstract Back to Event Medial prefrontal cortex ablation results in impaired spatial memory and hippocampal long-term potentiation with increased functional connectivity in vivo Amira Latif-Hernandez1*, Disha Shah2, Adrian Lo1, Tariq Ahmed1, Zsuzsanna Callaerts-Vegh1, Joris De Wit3, Annemie Van Der Linden2, Detlef Balschun1 and Rudi D'Hooge1 1 Katholieke Universiteit Leuven, Belgium 2 University of Antwerp, Biomedical Sciences, Belgium 3 VIB center for the biology of disease, Human genetics, Belgium Hippocampus (HC) and prefrontal cortex (PFC) are two brain regions that are essential for cognitive flexibility, ability to adapt to new situational demands (Hampshire, Chaudhry, Owen, & Roberts, 2012). PFC/HC projections are activated during attention and dissociable types of flexible behavior (Hok V, Lenck-Santini PP, Roux S, Save E, Muller RU, 2007). Furthermore, impaired PFC/HC communications might contribute to the cognitive rigidity observed in a variety of neurodegenerative disorders such as Alzheimer’s and frontotemporal dementia (Ittner & Götz, 2011). In the present study, we investigated the functional role of the PFC/HC network in cognitive flexibility by combining behavioral, electrophysiological, molecular readouts and brain imaging “in vivo” with excitotoxic inactivation (quinolinic acid, 30 mM). C57/BL6J mice were trained in the Morris water maze for ten consecutive days, a hippocampus-dependent spatial learning task. Immediately after acquisition learning, excitotoxic lesions were applied to the PFC (comprising infralimbic -IL/prelimbic –PrL-cortices) and cognitive flexibility was assessed during spatial reversal trials for five days. PFC lesions impaired reversal learning and affected search strategies to locate the hidden platform. Lesioned animals used a significantly higher percentage of non-spatial search strategies during reversal learning whereas control mice benefitted significantly more from spatial search strategies. Furthermore, the lesions in the IL/PrL area altered long-term potentiation (LTP) in the hippocampal CA1-region of slices prepared ex-vivo immediately after reversal learning. PFC-lesioned mice showed reduced hippocampal LTP and decreased amplitude in the Input/Output curve, as a measure of basal synaptic transmission. We also examined whether the reduced LTP was a consequence of the missing PFC input or rather an acute effect of the excitotoxic hyperactivation of NMDA receptors in the PFC caused by quinolinic acid. Importantly, twenty-four hours after the excitotoxic injection, hippocampal LTP was similar to controls. Moreover, the analysis of synaptic proteins revealed that PSD95, AMPA receptors and the NR2A subunit of the NMDA receptors were not affected in the hippocampi tissue from the lesioned mice compared with sham treated. In addition, resting state magnetic resonance imaging (rsfMRI) on day seven after the QA injection into PFC revealed stronger functional connectivity of the CA1 region of the HC with the rest brain areas, which might indicate an hippocampal hyperactivation caused by compensatory mechanisms to counteract the prefrontal impairment. In conclusion, mPFC lesions impair behavioral flexibility that is needed to adjust behavior to new environmental demands and hippocampal synaptic plasticity. Figure 1 Figure 2 Figure 3 Acknowledgements This work was supported by research grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G058714 and G0D76114) and an interdisciplinary research grant from KU Leuven (GOA 12/008).