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Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington’s Disease

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Abstract

Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington’s disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington’s disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD.

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Acknowledgements

We thank Ana Lopez and the staff of the animal care facility (Facultat de Medicina, Universitat de Barcelona) for their help. We are very grateful to Hubert Vaudry for his comments and language review.

Funding

Financial supports were obtained from the University of Girona (MPCUdG2016/036 to XX), Inserm (U1239 to DV), University of Rouen Normandy (to DV), Spanish Ministry of Economy and Competitiveness (MINECO) (SAF-2014-57160R, SAF-2017-88076-R and RETICS RD12/0019/0002 to JA), Fundació Marató TV3 to JA, Generalitat de Catalunya (2014SGR-968 to JA), and Instituto Carlos III to JA: Centro de Investigación Biomédica en Red sobre enfermedades neurodegenerativas (CIBERNED).

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Authors and Affiliations

  1. New Therapeutic Targets Group, Department of Medical Science, School of Medicine, Universitat de Girona, Girona, Spain

    N. Cabezas-Llobet, L. Vidal-Sancho & X. Xifró

  2. Departament de Biomedicina, Institut de Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

    L. Vidal-Sancho, M. Masana, J. Alberch & X. Xifró

  3. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    L. Vidal-Sancho, M. Masana, J. Alberch & X. Xifró

  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    L. Vidal-Sancho, M. Masana, J. Alberch & X. Xifró

  5. INRS—Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC, H7V 1B7, Canada

    A. Fournier

  6. International Associate Laboratory Samuel de Champlain, 531 boul. des Prairies, Laval, QC, H7 1B7, Canada

    A. Fournier

  7. Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Neuropeptides, Neuronal Death and Cell Plasticity Team, Normandie Univ, UNIROUEN, Inserm, 76000, Rouen, France

    D. Vaudry

  8. Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, C/ Emili Grahit 77, E-17003, Girona, Spain

    X. Xifró

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  1. N. Cabezas-Llobet
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  2. L. Vidal-Sancho
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  3. M. Masana
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Cabezas-Llobet, N., Vidal-Sancho, L., Masana, M. et al. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington’s Disease. Mol Neurobiol 55, 8263–8277 (2018). https://doi.org/10.1007/s12035-018-0972-5

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