Protein Kinase A deregulation in the medial prefrontal cortex impairs working memory in murine Oligophrenin1 deficiency
J. Neurosci.. 2017-10-13; 37(46): 11114-11126
Read on PubMed
1. J Neurosci. 2017 Nov 15;37(46):11114-11126. doi: 10.1523/JNEUROSCI.0351-17.2017.
Epub 2017 Oct 13.
Protein Kinase A Deregulation in the Medial Prefrontal Cortex Impairs Working
Memory in Murine Oligophrenin-1 Deficiency.
Zhang CL(1)(2), Aime M(1), Laheranne E(1), Houbaert X(1), El Oussini H(1), Martin
C(1), Lepleux M(1), Normand E(3), Chelly J(4)(5), Herzog E(1), Billuart P(4),
(1)Team Synapse in Cognition and.
(2)Neural Circuits for Spatial Navigation and Memory, Department of Neuroscience,
Institut Pasteur, 67400 Paris, France.
(3)Pole In Vivo, Institut Interdisciplinaire de Neuroscience, Centre National de
la Recherche Scientifique Centre National de la Recherche Scientifique Unité
Mixte de Recherche 5297, Université de Bordeaux, 33077 Bordeaux cedex, France.
(4)Centre National de la Recherche Scientifique, Université Paris Descartes,
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de
Recherche 8104, Institut Cochin, 75014 Paris, France.
(5)Team médecine “translationnelle et neurogénétique,” Institut de Génétique et
de Biologie Moléculaire et Cellulaire, Centre National de la Recherche
Scientifique Unité Mixte de Recherche 7104, Institut National de la Santé et de
la Recherche Médicale U964, Université de Strasbourg, 75015 Illkirch, France,
(6)Team Synapse in Cognition and .
Classical and systems genetics have identified wide networks of genes associated
with cognitive and neurodevelopmental diseases. In parallel to deciphering the
role of each of these genes in neuronal or synaptic function, evaluating the
response of neuronal and molecular networks to gene loss of function could reveal
some pathophysiological mechanisms potentially accessible to nongenetic
therapies. Loss of function of the Rho-GAP oligophrenin-1 is associated with
cognitive impairments in both human and mouse. Upregulation of both PKA and ROCK
has been reported in Ophn1-/y mice, but it remains unclear whether kinase
hyperactivity contributes to the behavioral phenotypes. In this study, we
thoroughly characterized a prominent perseveration phenotype displayed by
Ophn1-deficient mice using a Y-maze spatial working memory (SWM) test. We report
that Ophn1 deficiency in the mouse generated severe cognitive impairments,
characterized by both a high occurrence of perseverative behaviors and a lack of
deliberation during the SWM test. In vivo and in vitro pharmacological
experiments suggest that PKA dysregulation in the mPFC underlies cognitive
dysfunction in Ophn1-deficient mice, as assessed using a delayed spatial
alternation task results. Functionally, mPFC neuronal networks appeared to be
affected in a PKA-dependent manner, whereas hippocampal-PFC projections involved
in SWM were not affected in Ophn1-/y mice. Thus, we propose that discrete gene
mutations in intellectual disability might generate “secondary”
pathophysiological mechanisms, which are prone to become pharmacological targets
for curative strategies in adult patients.SIGNIFICANCE STATEMENT Here we report
that Ophn1 deficiency generates severe impairments in performance at spatial
working memory tests, characterized by a high occurrence of perseverative
behaviors and a lack of decision making. This cognitive deficit is consecutive to
PKA deregulation in the mPFC that prevents Ophn1 KO mice to exploit a correctly
acquired rule. Functionally, mPFC neuronal networks appear to be affected in a
PKA-dependent manner, whereas behaviorally important hippocampal projections were
preserved by the mutation. Thus, we propose that discrete gene mutations in
intellectual disability can generate “secondary” pathophysiological mechanisms
prone to become pharmacological targets for curative strategies in adults.
Copyright © 2017 the authors 0270-6474/17/3711114-13$15.00/0.
PMID: 29030432 [Indexed for MEDLINE]