Brain Advance Access published online on October 16, 2008
Brain, doi:10.1093/brain/awn253
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A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice
1Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, 2CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 322-0012, 3Department of Molecular Therapy, 4Department of Ultrastructure Research and 5Department of Cell Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
Correspondence to:
Masayuki Sekiguchi, Department of Degenerative Neurological Diseases, National Centre of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan E-mail: elec1{at}ncnp.go.jp; sekiguch{at}ncnp.go.jp
Duchenne muscular dystrophy (DMD) is accompanied by cognitive deficits and psychiatric symptoms. In the brain, dystrophin, the protein responsible for DMD, is localized to a subset of GABAergic synapses, but its role in brain function has not fully been addressed. Here, we report that defensive behaviour, a response to danger or a threat, is enhanced in dystrophin-deficient mdx mice. Mdx mice consistently showed potent defensive freezing responses to a brief restraint that never induced such responses in wild-type mice. Unconditioned and conditioned defensive responses to electrical footshock were also enhanced in mdx mice. No outstanding abnormality was evident in the performances of mdx mice in the elevated plus maze test, suggesting that the anxiety state is not altered in mdx mice. We found that, in mdx mice, dystrophin is expressed in the amygdala, and that, in the basolateral nucleus (BLA), the numbers of GABAA receptor 
2 subunit clusters are reduced. In BLA pyramidal neurons, the frequency of norepinephrine-induced GABAergic inhibitory synaptic currents was reduced markedly in mdx mice. Morpholino oligonucleotide-induced expression of truncated dystrophin in the brains of mdx mice, but not in the muscle, ameliorated the abnormal freezing response to restraint. These results suggest that a deficit of brain dystrophin induces an alteration of amygdala local inhibitory neuronal circuits and enhancement of fear-motivated defensive behaviours in mice.
Key Words: GABAergic synapse; scaffolding proteins; dystrophin; defensive behaviour; amygdala
Abbreviations: BLA, basolateral nucleus of amygdala; DMD, Duchenne muscular dystrophy; IPSC, inhibitory postsynaptic current; IQ, intelligence quotient; NE, norepinephrine; PD, postnatal day; WT, wild-type
Received April 9, 2008. Revised September 10, 2008. Accepted September 10, 2008.