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M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition.

Koshimizu H, Leiter LM, Miyakawa T - Mol Brain (2012)

Bottom Line: However, other behaviorally significant roles of M4R remain unclear.M4R KO mice also displayed normal performance in the Morris water maze test.Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.

ABSTRACT

Background: In the central nervous system (CNS), the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M4 muscarinic receptor knockout (M4R KO) mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI)-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M4R remain unclear.

Results: In this study, to further investigate precise functional roles of M4R in the CNS, M4R KO mice were subjected to a battery of behavioral tests. M4R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M4R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M4R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M4R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M4R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M4R KO mice demonstrated normal startle response. M4R KO mice also displayed normal performance in the Morris water maze test.

Conclusions: These findings indicate that M4R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia.

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Normal spatial reference, working, and episodic-like memory of M4R KO mice in the Morris water maze. (A-E) No significant differences in the conventional hidden platform version of the Morris water maze were detected between genotypes. Escape latency (A), swimming speed (B), and time spent in the perimeter of the pool (C) did not differ significantly between the two genotypes during either original or reversal learning. M4R KO mice, n = 13; wild-type mice, n = 14. In probe trials, both M4R KO mice and wild-type mice selectively searched the location where the platform had been located. M4R KO mice, n = 11; wild-type mice, n = 12. (D) Both genotypes spent significantly more time in the training quadrant (black bars) compared with the other quadrants (opposite quadrant, white bars; right quadrant, dark gray bars; left quadrant, light gray bars) in the probe trials conducted after original training. (E) Also, both genotypes crossed the training site significantly more often than the equivalent sites in the other three quadrants in the probe trials. (F) No significant difference in the delayed matching-to-place (DMP) task of the Morris water maze was detected between genotypes. M4R KO mice showed normal latency in the first five trials of new platform training, averaged over six training sessions. M4R KO mice n = 13; wild-type mice, n = 14.
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Figure 5: Normal spatial reference, working, and episodic-like memory of M4R KO mice in the Morris water maze. (A-E) No significant differences in the conventional hidden platform version of the Morris water maze were detected between genotypes. Escape latency (A), swimming speed (B), and time spent in the perimeter of the pool (C) did not differ significantly between the two genotypes during either original or reversal learning. M4R KO mice, n = 13; wild-type mice, n = 14. In probe trials, both M4R KO mice and wild-type mice selectively searched the location where the platform had been located. M4R KO mice, n = 11; wild-type mice, n = 12. (D) Both genotypes spent significantly more time in the training quadrant (black bars) compared with the other quadrants (opposite quadrant, white bars; right quadrant, dark gray bars; left quadrant, light gray bars) in the probe trials conducted after original training. (E) Also, both genotypes crossed the training site significantly more often than the equivalent sites in the other three quadrants in the probe trials. (F) No significant difference in the delayed matching-to-place (DMP) task of the Morris water maze was detected between genotypes. M4R KO mice showed normal latency in the first five trials of new platform training, averaged over six training sessions. M4R KO mice n = 13; wild-type mice, n = 14.

Mentions: Finally, M4R KO mice were subjected to the conventional hidden platform version and DMP task of the Morris water maze test to evaluate spatial reference, working, and episodic-like memory in mice. No significant differences between genotypes were observed in latency to platform (time required to reach the platform) during original learning (F1, 25 = 0.021, P = 0.8855) or reversal learning (F1, 25 = 0.774, P = 0.3873; Figure 5A), swimming speed during original learning (F1, 25 = 1.667, P = 0.2085) or reversal learning (F1, 25 = 0.912, P = 0.3486; Figure 5B), or time spent at the perimeter of the pool during original learning (F1, 25 = 2.713, P = 0.1120) or reversal learning (F1, 25 = 0.012, P = 0.9136; Figure 5C). During probe trials, in which the platform was removed, both M4R KO mice and wild-type mice selectively searched for the location where the platform had been located. Both genotypes spent significantly more time in the training quadrant compared with the other quadrants (M4R KO mice, F3, 40 = 6.52905, P < 0.001; wild-type mice, F3, 36 = 16.03608, P = 0.001) in the probe trials conducted after original training (Figure 5D). Also, both genotypes crossed the training site significantly more often than the equivalent sites in the other three quadrants (M4R KO mice, F3, 40 = 4.06293, P < 0.001; wild-type mice, F3, 36 = 8.85831, P = 0.013) in the probe trials (Figure 5E). In the DMP task, no significant difference in latency to platform was observed between genotypes (P = 0.6180; Figure 5F). These data indicate that lack of M4R does not induce impairments in spatial reference, working, or episodic-like memory in mice.


M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition.

Koshimizu H, Leiter LM, Miyakawa T - Mol Brain (2012)

Normal spatial reference, working, and episodic-like memory of M4R KO mice in the Morris water maze. (A-E) No significant differences in the conventional hidden platform version of the Morris water maze were detected between genotypes. Escape latency (A), swimming speed (B), and time spent in the perimeter of the pool (C) did not differ significantly between the two genotypes during either original or reversal learning. M4R KO mice, n = 13; wild-type mice, n = 14. In probe trials, both M4R KO mice and wild-type mice selectively searched the location where the platform had been located. M4R KO mice, n = 11; wild-type mice, n = 12. (D) Both genotypes spent significantly more time in the training quadrant (black bars) compared with the other quadrants (opposite quadrant, white bars; right quadrant, dark gray bars; left quadrant, light gray bars) in the probe trials conducted after original training. (E) Also, both genotypes crossed the training site significantly more often than the equivalent sites in the other three quadrants in the probe trials. (F) No significant difference in the delayed matching-to-place (DMP) task of the Morris water maze was detected between genotypes. M4R KO mice showed normal latency in the first five trials of new platform training, averaged over six training sessions. M4R KO mice n = 13; wild-type mice, n = 14.
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Figure 5: Normal spatial reference, working, and episodic-like memory of M4R KO mice in the Morris water maze. (A-E) No significant differences in the conventional hidden platform version of the Morris water maze were detected between genotypes. Escape latency (A), swimming speed (B), and time spent in the perimeter of the pool (C) did not differ significantly between the two genotypes during either original or reversal learning. M4R KO mice, n = 13; wild-type mice, n = 14. In probe trials, both M4R KO mice and wild-type mice selectively searched the location where the platform had been located. M4R KO mice, n = 11; wild-type mice, n = 12. (D) Both genotypes spent significantly more time in the training quadrant (black bars) compared with the other quadrants (opposite quadrant, white bars; right quadrant, dark gray bars; left quadrant, light gray bars) in the probe trials conducted after original training. (E) Also, both genotypes crossed the training site significantly more often than the equivalent sites in the other three quadrants in the probe trials. (F) No significant difference in the delayed matching-to-place (DMP) task of the Morris water maze was detected between genotypes. M4R KO mice showed normal latency in the first five trials of new platform training, averaged over six training sessions. M4R KO mice n = 13; wild-type mice, n = 14.
Mentions: Finally, M4R KO mice were subjected to the conventional hidden platform version and DMP task of the Morris water maze test to evaluate spatial reference, working, and episodic-like memory in mice. No significant differences between genotypes were observed in latency to platform (time required to reach the platform) during original learning (F1, 25 = 0.021, P = 0.8855) or reversal learning (F1, 25 = 0.774, P = 0.3873; Figure 5A), swimming speed during original learning (F1, 25 = 1.667, P = 0.2085) or reversal learning (F1, 25 = 0.912, P = 0.3486; Figure 5B), or time spent at the perimeter of the pool during original learning (F1, 25 = 2.713, P = 0.1120) or reversal learning (F1, 25 = 0.012, P = 0.9136; Figure 5C). During probe trials, in which the platform was removed, both M4R KO mice and wild-type mice selectively searched for the location where the platform had been located. Both genotypes spent significantly more time in the training quadrant compared with the other quadrants (M4R KO mice, F3, 40 = 6.52905, P < 0.001; wild-type mice, F3, 36 = 16.03608, P = 0.001) in the probe trials conducted after original training (Figure 5D). Also, both genotypes crossed the training site significantly more often than the equivalent sites in the other three quadrants (M4R KO mice, F3, 40 = 4.06293, P < 0.001; wild-type mice, F3, 36 = 8.85831, P = 0.013) in the probe trials (Figure 5E). In the DMP task, no significant difference in latency to platform was observed between genotypes (P = 0.6180; Figure 5F). These data indicate that lack of M4R does not induce impairments in spatial reference, working, or episodic-like memory in mice.

Bottom Line: However, other behaviorally significant roles of M4R remain unclear.M4R KO mice also displayed normal performance in the Morris water maze test.Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.

ABSTRACT

Background: In the central nervous system (CNS), the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M4 muscarinic receptor knockout (M4R KO) mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI)-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M4R remain unclear.

Results: In this study, to further investigate precise functional roles of M4R in the CNS, M4R KO mice were subjected to a battery of behavioral tests. M4R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M4R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M4R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M4R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M4R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M4R KO mice demonstrated normal startle response. M4R KO mice also displayed normal performance in the Morris water maze test.

Conclusions: These findings indicate that M4R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia.

Show MeSH
Related in: MedlinePlus