Behavioral and neurochemical characterization of mice deficient in the N-type Ca2+ channel alpha1B subunit.
N-type voltage-dependent calcium channels (VDCCs) play an important role in neurotransmission, synaptic plasticity, and brain development. They are composed of several subunits named alpha(1), alpha(2), delta, beta and gamma. The alpha(1) subunit is essential for channel functions and determines fundamental channel properties. Since N-type VDCC are critically involved in the release of neurotransmitters and clinical relevance, we predicted that alpha(1) subunit KO mice would show several alterations in behavior. In the present study, we investigated neuronal functions in mice lacking the alpha(1B) (Ca(V)2.2) subunit of the N-type calcium channels. Ca(V)2.2(-/-) mice exhibited a significant increase in locomotion on an activity wheel during the dark phase. Furthermore, when challenged with apomorphine, mutant mice showed enhanced locomotor activity. Cognitive functions were examined using a Y-maze task for short-term memory and a passive avoidance task for long-term memory. The Y-maze revealed no differences in spontaneous alternation behavior between mutant and wild-type mice. The passive avoidance test revealed that the latency time in mutant mice was significantly decreased. The mutant mice showed prepulse inhibition deficits reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. Decreases in baseline levels of dopamine and serotonin within the striata and frontal cortices of mutant mice were also observed. These results suggest that Ca(2+) in the central nervous system modulates various neurophysiological functions, such as locomotor activity, long-term memory, and sensorimotor gating through the alpha(1B) subunit of the N-type calcium channels.
Nakagawasai
Osamu
O
Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. osamun@tohoku-pharm.ac.jp
Onogi
Hiroshi
H
Mitazaki
Satoru
S
Sato
Atsushi
A
Watanabe
Kenya
K
Saito
Hiroko
H
Murai
Shigeo
S
Nakaya
Kota
K
Murakami
Manabu
M
Takahashi
Eiki
E
Tan-No
Koichi
K
Tadano
Takeshi
T
D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000172:deficiency*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002940:Circadian Rhythm / Q000235:genetics; D018491:Dopamine Agonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D007266:Inhibition, Psychological; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D045442:Rotarod Performance Test / Q000379:methods
D015306:Biogenic Monoamines; C500963:Cacna1b protein, mouse; D020864:Calcium Channels, N-Type; D018491:Dopamine Agonists; D001058:Apomorphine