Deletion of N-type Ca2+ Channel Cav2.2 Results in Hyperaggressive Behaviors in Mice

Abstract

Voltage-dependent N-type Ca2؉ channels play important roles in the regulation of diverse neuronal functions in the brain, but little is known about its role in social aggressive behaviors. Mice lacking the ␣1B subunit (Ca v 2.2) of N-type Ca 2؉ channels showed markedly enhanced aggressive behaviors to an intruder mouse in the resident-intruder test. The dorsal raphe nucleus (DRN), which contains serotonin neurons, is known to be involved in aggression in animals. We thus examined the DRN neurons in the Ca v 2. (2-6), there was no study of the role of N-type Ca 2ϩ channels in aggression. It is believed that most social animals possess neural mechanisms for the control of aggression, which is essential for maintenance of beneficial relationships among members in a community. Aggression is considered a complex social behavior influenced by both internal (e.g. hormones or genes) and external stimuli (e.g. drive, TV, and frustration etc.) (7). Deficit of the control mechanisms for suppression of aggression might be implicated in the development of violence in various psychiatric disorders, such as attention deficit/hyperactivity disorder (ADHD) and personality disorders (8, 9).The modulation of aggression has been associated with a change in the central serotonin (5-HT) system at the dorsal raphe nucleus (DRN) (10 -14). In the DRN, the 5-HT neuronal activity showing a slow and regular firing pattern (15-17) is known to be influenced by ␥-aminobutyric acid (GABA), 5-HT 1A autoreceptor, and noradrenergic input (17). Furthermore, the modulation of these signals in the DRN affected aggression behaviors in animals (10 -13, 18, 19).It has been shown that the Ca v 2.2 is highly expressed in the DRN of adult rats (20). However, the role of Ca v 2.2 in the DRN has not been examined, nor has the involvement of Ca v 2.2 in the regulation of aggression. Therefore, we have characterized aggression behaviors of Ca v 2.2 Ϫ/Ϫ mice and investigated the properties of the Ca v 2.2 Ϫ/Ϫ DRN neurons. Interestingly, the Ca v 2.2 Ϫ/Ϫ mice exhibited an enhanced aggressive behavior and a reduced inhibitory transmission in the DRN. In addition, Ca v 2.2 Ϫ/Ϫ mice showed an increased level of arginine vasopressin (AVP) in the cerebrospinal fluid (CSF), together with an increase of 5-HT in the hypothalamus. Our results suggest a possibility that the N-type Ca 2ϩ channel plays a critical role in the suppression of aggressive behaviors. EXPERIMENTAL PROCEDURESAnimals-All of the animals were handled in accordance with the animal care and use guidelines of the Korea Institute of * This work was supported by a National Honor Scientist grant from the Ministry of Science and Technology, Korea, and the Chemoinformatics program, the Center-of-Excellence program, and the Top-Brand program in Korea Institute of Science and Technology, Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate t...

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