A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice

Abstract

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 GABA(A) receptor alpha2 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.

A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery

“…Collectively, these results correspond with findings that highlight the effects of stress exposure-induced amygdala modulation of learning and memory processes (36). More specifically, increased freezing responses have been associated with altered amygdalar activity (37,38); thus the increased freezing exhibited by tKO mice corresponds to the increased stress-potentiated ASR and to the alterations in amygdalar functions described in detail below. The comparable freezing exhibited by both genotypes in the context test may result from an interaction between enhanced amygdalar functions and a stress-induced deficit in hippocampal functions.…”

Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations

“…In the mdx mouse, lack of Dp427 is associated with reduced receptor clustering, impairing specific amygdala GABAergic transmission and enhancing defensive behaviour in response to danger. 32 In contrast, Dp140 localizes in glial cells and Dp71 is expressed in the perivascular astrocytes, which is required for anchoring aquaporin-4. Loss of Dp71 is associated with reduced levels of aquaporin-4, thus altering transmembrane water permeability.…”

The dystrophin gene and cognitive function in the general population

“…It has been shown that this form of protein dystrophin colocalizes with inhibitory GABA receptor clusters at the postsynaptic membranes of hippocampal and neocortical pyramidal neurons where the synapse function is modulated. [45][46][47][48] According to various studies this dystrophin isoform has a stabilizing effect on the GABA receptors by limiting their lateral diffusion outside the synapse. 49,50 Importance of GABA receptors for the regulation of cognition, emotion and memory is increasingly being recognized.…”