Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice
Autor: | Kim Fejgin, Michelle Rosgaard Birknow, Kenneth Vielsted Christensen, Peter H. Larsen, Francois Gastambide, Jesper F. Bastlund, Michael Didriksen, Hannah M. Grayton, Jan Egebjerg, Francesc Artigas, Tine B. Stensbøl, Jes B. Lauridsen, Simon R. O. Nilsson, Jacob Nielsen, Vibeke Nielsen, Pekka Kallunki, Pau Celada, Thomas Werge, Noemí Santana |
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Přispěvatelé: | Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, Danish National Advanced Technology Foundation, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Salud Mental (España) |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male medicine.medical_specialty Startle response Aging Reflex Startle Prefrontal Cortex AMPA receptor Motor Activity Receptors N-Methyl-D-Aspartate 03 medical and health sciences 0302 clinical medicine Dopamine Internal medicine DiGeorge syndrome medicine DiGeorge Syndrome Evoked Potentials Auditory Brain Stem Animals Pharmacology (medical) Receptors AMPA Prefrontal cortex Biological Psychiatry Prepulse inhibition Sensory gating medicine.diagnostic_test Sensory Gating medicine.disease Corpus Striatum Mice Inbred C57BL Psychiatry and Mental health Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Schizophrenia Auditory Perception 3 4-Dihydroxyphenylacetic Acid Psychology Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery medicine.drug Research Paper |
Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
ISSN: | 1488-2434 |
Popis: | [Background] The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. [Methods] We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. [Results] We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist–induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. [Limitations] The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. [Conclusion] The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS. The research leading to these results was conducted as part of NEWMEDS and received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement 115008, of which resources are composed of an EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). This work was further supported by grants from the Danish Advanced Technology Foundation (File no. 001-2009-2) and by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). |
Databáze: | OpenAIRE |
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