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The Journal of Neuroscience, July 15, 2001, 21(14):5239-5250
Hyperactivity and Intact Hippocampus-Dependent Learning in Mice
Lacking the M1 Muscarinic Acetylcholine Receptor
Tsuyoshi
Miyakawa1,
Masahisa
Yamada2,
Alokesh
Duttaroy2, and
Jürgen
Wess2
1 Department of Pharmacology and Center for Molecular
Neuroscience, Vanderbilt University Medical Center, Nashville,
Tennessee 37205, and 2 Laboratory of Bioorganic Chemistry,
National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, Maryland 20892
Members of the muscarinic acetylcholine receptor family are thought
to play key roles in the regulation of a large number of important
functions of the CNS. However, the precise roles of the individual
muscarinic receptor subtypes in modulating these processes are not well
understood at present, primarily because of the lack of ligands with
sufficient receptor subtype selectivity. To investigate the behavioral
significance of the M1 muscarinic receptor
(M1R), which is abundantly expressed in the forebrain, we
subjected M1 receptor-deficient mice
(M1R / mice) to a battery
of behavioral tests. M1R/
mice showed no significant impairments in neurological reflexes, motor
coordination, pain sensitivity, and prepulse inhibition. Strikingly,
however, M1R/ mice
consistently exhibited a pronounced increase in locomotor activity in
various tests, including open field, elevated plus maze, and light/dark
transition tests. Moreover,
M1R/ mice showed reduced
immobilization in the Porsolt forced swim test and reduced levels of
freezing after inescapable footshocks, suggesting that
M1R/ mice are hyperactive
under stressful conditions as well. An increased number of social
contacts was observed in a social interaction test. Surprisingly,
M1R/ mice displayed no
significant cognitive impairments in the Morris water maze and in
contextual fear conditioning.
M1R/ mice showed slight
performance deficits in auditory-cued fear conditioning and in an
eight-arm radial maze, most likely because of the hyperactivity
phenotype displayed by the
M1R/ mice. Our results
indicate that M1 muscarinic receptors play an important
role in the regulation of locomotor activity but appear to be less
critical for cognitive processes, as generally assumed.
Key words:
acetylcholine; muscarinic receptor; M1
receptor; hyperactivity; learning; gene targeting; knock-out; behavioral phenotyping
Copyright © 2001 Society for Neuroscience 0270-6474/01/21145239-12$05.00/0
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