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
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
Externí odkaz: