The effect of mGlu8 deficiency in animal models of psychiatric diseases.
The metabotropic glutamate receptor subtype 8 (mGlu(8)) is presynaptically located and regulates the release of the transmitter. Dysfunctions of this mechanism are involved in the pathophysiology of different psychiatric disorders. mGlu(8) deficient mice have been previously investigated in a range of studies, but the results are contradictory and there are still many open questions. Therefore, we tested mGlu(8)-deficient animals in different behavioral tasks that are commonly used in neuropsychiatric research. Our results show a robust contextual fear deficit in mGlu(8)-deficient mice. Furthermore, novel object recognition, chlordiazepoxide-facilitated extinction of operant conditioning and the acoustic startle response were attenuated by mGlu(8) deficiency. We found no changes in sensory processing, locomotor activity, prepulse inhibition, phencyclidine-induced changes in locomotion or prepulse inhibition, operant conditioning, conditioned fear to a discrete cue or in animal models of innate fear and post-traumatic stress disorder. We conclude that mGlu(8) might be a potential target for disorders with pathophysiological changes in brain areas where mGlu(8) modulates glutamate and gamma-amino butyric acid (GABA) transmission. Our data especially point to anxiety disorders involving exaggerated contextual fear, such as generalized anxiety disorders, and to conditions with disturbed declarative memory.
Fendt
M
M
Novartis Institutes for BioMedical Research, Neuroscience DA, 4056 Basel, Switzerland. markus.fendt@novartis.com
Bürki
H
H
Imobersteg
S
S
van der Putten
H
H
McAllister
K
K
Leslie
J C
JC
Shaw
D
D
Hölscher
C
C
D000818:Animals; D001008:Anxiety Disorders / Q000378:metabolism* / Q000523:psychology*; D002707:Chlordiazepoxide / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D005108:Extinction, Psychological; D005239:Fear; D006948:Hyperkinesis / Q000139:chemically induced / Q000503:physiopathology; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D010364:Pattern Recognition, Visual; D010622:Phencyclidine; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency*; D013216:Reflex, Startle
D018094:Receptors, Metabotropic Glutamate; C111435:metabotropic glutamate receptor 8; D002707:Chlordiazepoxide; D010622:Phencyclidine