Neuropsychopharmacology. 2016 Feb;41(3):726-35.
Metabotropic Glutamate Receptor Subtype 7 in the Bed Nucleus of the Stria Terminalis is Essential for Intermale Aggression
Miwako Masugi-Tokita1,2,3, Peter J. Flor4, and Mitsuhiro Kawata3,5
1World Premier International Research Initiative–Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan
2Institute for Virus Research, Kyoto University, Kyoto, Japan
3Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
4Faculty of Biology and Preclinical Medicine, University of Regensburg, Regensburg, Germany
5School of Health Sciences, Bukkyo University, Kyoto, Japan
Metabotropic glutamate receptor subtype 7 (mGluR7) is a member of group III mGluRs, which localize to the presynaptic active zones of the mammalian central nervous system. Although histological, genetic, and electrophysiological studies ensure the importance of mGluR7, its roles in behavior and physiology remain largely unknown. Using a resident-intruder paradigm, we found a severe reduction in intermale aggressive behavior in mGluR7 knockout (KO) mice. We also found alterations in other social behaviors in male mGluR7 KO mice, including sexual behavior toward male intruders. Because olfaction is critical for rodent social behavior, including aggression, we performed an olfaction test, finding that mGluR7 KO mice failed to show interest in the smell of male urine. To clarify the olfactory deficit, we then exposed mice to urine and analyzed c-Fos-immunoreactivity, discovering a remarkable reduction in neural activity in the bed nucleus of the stria terminalis (BNST) of mGluR7 KO mice. Finally, intra-BNST administration of the mGluR7-selective antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) also reproduced the phenotype of mGluR7 KO mice, including reduced aggression and altered social interaction. Thus, mGluR7 may work as an “enhancer of neural activity” in the BNST and is important for intermale aggression. Our findings demonstrate that mGluR7 is essential for social behavior and innate behavior. Our study on mGluR7 in the BNST will shed light on future therapies for emotional disorders in humans.
Metabotropic glutamate receptor subtype 7 (mGluR7) localizes to the presynaptic active zone, and has been postulated to be one of the most important mGluRs. Although unique distribution (Shigemoto et al., 1996) and peculiar electrophysiological properties (Pelkey et al., 2005; Pelkey et al., 2008) have been reported, the physiological relevance of this receptor remains to be elucidated. The purpose of this study was to uncover the in vivo function of mGluR7, and link the relevance.
Using mGluR7 knockout (KO) mice, we show that mGluR7 is essential for intermale aggression. Our observation also implies that mGluR7 functions as an “enhancer of excitation” in the posterior division of the bed nucleus of the stria terminalis (BNSTp).
To reveal why aggression is defective in mGluR7 KO mice, we tested olfaction, which is important for social recognition, and found an altered urine preference. Then, we show a remarkable reduction in neural responses to urine in the BNSTp of mGluR7 KO mice. We were also able to reproduce the mGluR7 KO phenotype by microinjection of a selective mGluR7 antagonist (MMPIP) into the BNSTp. This pharmacological approach ensured the reliability of the KO study. Thus, robust aggressive behavior requires mGluR7 in the BNSTp. In addition, the results clearly exclude the possibility that the impaired aggression is caused by anomalous neural circuits in the KO mice.
Previously, we reported that mGluR7 KO mice show a deficit in fear response (Masugi et al., 1999). In addition, many papers have discussed the link between mGluR7 and anxiety. Moreover, mGluR7 is anticipated to be associated with seizures and several human diseases, including Alzheimer’s disease (Gu et al., 2014), and some of the intracellular mechanisms of this phenotype have been revealed (Bertaso et al., 2008).
The significance of this study certainly extends beyond the mGluR field because we reveal a novel physiological role of mGluR7 and also the mechanism involved. Surprisingly, the presynaptic molecule mGluR7 is crucial for the postsynaptic excitability of groups of BNST neurons and for the regulation of aggressive behavior. Although mGluRs are regarded as neuronal modulators, our results show that mGluR7 strongly affects the intensity of neural transmission. Our findings shed light on the novel principles of synaptic modulation with mGluR in the neural circuits, and would arise investigator’s interests in this field. We demonstrate that mGluR7 may regulate emotions and instinctive behaviors. Furthermore, our study may help in the discovery of novel therapies for emotional disorders in humans.
The anterior division of the BNST has lately attracted considerable attention following the discovery that it regulates fear (Kim et al., 2013), and motivational states (Jennings et al., 2013a; Jennings et al., 2013b). In contrast, the cytoarchitecture and function of the BNSTp is still poorly understood. Moreover, only fragmentary and controversial evidence suggests its involvement in aggression. We focused on the role of mGluR7 in the BNSTp in the regulation of social behavior, as exemplified by intermale aggression. We believe that our current study will help to unravel the physiological roles of the BNSTp in instinctive behaviors, which have not been previously investigated.
Although, further investigation is required, we would like to present models for how mGluR7 functions as an enhancer of excitation (Figure 1).
Figure 1. Models for how mGluR7 works as an enhancer of excitation. (A) mGluR7 shows target cell specificity. In case mGluR7 positive axons are glutamatergic, which decorate a specific type of GABAergic interneurons, mGluR7 would work as an autoreceptor to inhibit glutamate release. These regulatory mechanisms are crucial for appropriately recognize the input. In mGluR7 KO mice, hyper activation of interneurons causes c-Fos reduction, and impaired recognition. (B) In case mGluR7 express glutamatergic axon terminals connect to the excitatory neurons, mGluR7 is assumed to have facilitatory effect. The synaptic transmission of mGluR7- internalized presynapses might be different from those presynapses that genuinely lack mGluR7. In mGluR7 KO mice deficit in enhancement of excitation cause the reduced c-Fos expression.
Bertaso, F., Zhang, C., Scheschonka, A., de Bock, F., Fontanaud, P., Marin, P., Huganir, R.L., Betz, H., Bockaert, J., Fagni, L., Lerner-Natoli, M., 2008. PICK1 uncoupling from mGluR7a causes absence-like seizures. Nat Neurosci 11, 940-948.
Gu, Z., Cheng, J., Zhong, P., Qin, L., Liu, W., Yan, Z., 2014. Abeta selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer’s disease. J Neurosci 34, 13614-13628.
Jennings, J.H., Rizzi, G., Stamatakis, A.M., Ung, R.L., Stuber, G.D., 2013a. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517-1521.
Jennings, J.H., Sparta, D.R., Stamatakis, A.M., Ung, R.L., Pleil, K.E., Kash, T.L., Stuber, G.D., 2013b. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224-228.
Kim, S.Y., Adhikari, A., Lee, S.Y., Marshel, J.H., Kim, C.K., Mallory, C.S., Lo, M., Pak, S., Mattis, J., Lim, B.K., Malenka, R.C., Warden, M.R., Neve, R., Tye, K.M., Deisseroth, K., 2013. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219-223.
Masugi, M., Yokoi, M., Shigemoto, R., Muguruma, K., Watanabe, Y., Sansig, G., van der Putten, H., Nakanishi, S., 1999. Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion. J. Neurosci. 19, 955-963.
Pelkey, K.A., Lavezzari, G., Racca, C., Roche, K.W., McBain, C.J., 2005. mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 46, 89-102.
Pelkey, K.A., Topolnik, L., Yuan, X.Q., Lacaille, J.C., McBain, C.J., 2008. State-dependent cAMP sensitivity of presynaptic function underlies metaplasticity in a hippocampal feedforward inhibitory circuit. Neuron 60, 980-987.
Shigemoto, R., Kulik, A., Roberts, J.D., Ohishi, H., Nusser, Z., Kaneko, T., Somogyi, P., 1996. Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381, 523-525.
Miwako Masugi-Tokita, M.D., Ph.D.
World Premier International Research Initiative–Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University
Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501, Japan
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