Abstract
The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.
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Acknowledgments
We thank Drs. Cyril Herry, Andréas Luthi and Andrew Penn for fruitful discussions and corrections of the manuscript. We are grateful to Dr. P. Billuart and J. Chelly for their help and for providing us with Il1rapl1 mutant mice, and Dr. Jiyun Peng for helping in the tracking of mouse activities. We acknowledge Ed Boyden, Ph.D., and the Massachusetts Institute of Technology for kindly providing AAV-ArchT constructs to the research community and Dr. C. Herry for providing us with AAV viruses. We also thank the Pole in vivo and animal facilities of the Bordeaux University for the animal care. The microscopy was done in the Bordeaux Imaging Centre of the University of Bordeaux, with the help of Sébastien Marais. This study was supported by grants from the Agence Nationale pour la Recherche (ANR-10-BLAN-1434, ANR-12-JSV4-0005-01, ANR-12-SAMA-001-03 and ANR-10-LABX-43 BRAIN to E.H. and Y.H.), the European Neuroscience Institutes Network (Y.H.), the Gencodys FP7 program (Y.H.).
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C.-L. Zhang and X. Houbaert contributed equally to the work.
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Supplementary Fig. 1: Effect of functional inactivation of cHPC or BLA on contextual fear expression. a Experimental protocol. WT mice were conditioned, and tested for contextual fear response 24 h later (“before”). In vivo muscimol applications were done 24 h later, and mice tested 1-2 h and 24 h later (“after”). b Cannula positions of included animals for cHPC (left) or BLA (right) inactivation. c cHPC and BLA impairment by muscimol infusion temporally affects the intensity of the contextual fear conditioned response.Supplementary Fig. 2: Pharmacological BLA activation during contextual fear expression in Il1rapl1 WT and KO mice. a Experimental protocol. b Cannula positions in Il1rapl1 KO and WT animals. Pharmacological activation of BLA induced a transient increase of freezing levels in KO animals (Fig. 7C). Two-way ANOVA revealed a significant effect of genotype (ANOVA F (1,45) = 12,362; p = 0.001) and of treatment (ANOVA F (2,45) = 5,555; p = 0.007), but no interaction between genotype and treatment (ANOVA F (2,45) = 0,318; p = 0.729) as the treatment did not have an significant effect on WT freezing levels. SNK post hoc multiple comparisons were used to test for differences between groups. They showed an effect of treatment on KO freezing levels (SNK before vs. 1–2 h after; p < 0.05). The difference observed between WT and KO animals before treatment (SNK before WT vs. KO; p < 0.05) disappeared after illumination, KO animals reaching similar levels to WT animals (SNK 1–2 h after WT vs. KO; p > 0.05). 24 h after treatment, a difference between WT and KO animals is observed again (SNK 24 h later WT vs. KO; p < 0.05), showing that BLA activation transiently rescues KO phenotype.Supplementary Fig. 3: Infection sites of in vitro optogenetic experiments. The maximal surface of each infection site was assessed by GFP expression, and reported according to the bregma position for all used WT and KO animals. Note that infection sites always included the caudal CA1 region of the hippocampus and often the ventral subiculum.Supplementary Fig. 4: Lack of BLA neuronal activation following hippocampal projections in Il1rapl1 KO mice. A: Experimental protocol. WT and KO GAD-67eGPF mice were infected with AAV-ChR2 in the cHPC. Three weeks later, fiber optics were positioned under anesthesia and repetitive bursts of 460 nm light pulses were applied at the infection sites. 90 min after illumination, animals were sacrificed and prepared for C-Fos labeling in the BLA. B: counting of C-Fos positive cells expressing or not eGFP was performed in WT and KO mice (3 and 3), and showed a higher proportion of double labeled cells in the KO mice. (PDF 4466 kb)
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Zhang, CL., Houbaert, X., Lepleux, M. et al. The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability. Brain Struct Funct 220, 3673–3682 (2015). https://doi.org/10.1007/s00429-014-0882-x
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DOI: https://doi.org/10.1007/s00429-014-0882-x