Selective Reduction in the Nicotinic Acetylcholine Receptor and Dystroglycan at the Postsynaptic Apparatus ofmdxMouse Superior Cervical Ganglion

Abstract

Our previous data suggested that in mouse sympathetic superior cervical ganglion (SCG) the dystrophin-dystroglycan complex may be involved in the stabilization of the nicotinic acetylcholine receptor (nAChR) clusters. Here we used SCG of dystrophic mdx mice, which express only the shorter isoforms of dystrophin (Dys), to investigate whether the lack of the full-length dystrophin (Dp427) could affect the localization of the dystroglycan and the alpha3 nAChR subunit (alpha3AChR) at the postsynaptic apparatus. We found a selective reduction in intraganglionic postsynaptic specializations immunopositive for alpha3AChR and for alpha- and beta-dystroglycan compared with the wild-type. Moreover, in mdx mice, unlike the wild-type, the disassembly of intraganglionic synapses induced by postganglionic nerve crush occurred at the slower rate and was not preceded by the loss of immunoreactivity for Dys isoforms, beta-dystroglycan, and alpha3AChR. These data indicate that the absence of Dp427 at the intraganglionic postsynaptic apparatus of mdx mouse SCG interferes with the presence of both dystroglycan and nAChR clusters at these sites and affects the rate of synapse disassembly induced by postganglionic nerve crush. Moreover, they suggest that the decrease in ganglionic nAChR may be one of the factors responsible for autonomic imbalance described in Duchenne muscular dystrophy patients.

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

“…These results contrast with the presence of fulllength utrophin at the nmj, where it co-localizes with muscle-type nAChRs and functions in their stabilization (Khurana et al, 1991;Ohlendieck et al, 1991;Deconinck et al, 1997;Grady et al, 1997;Slater et al, 1997;Banks et al, 2003). Surprisingly, our results at α3-containing nAChR synapses in CG neurons also differ from reports that full-length dystrophin is present at a subset of α3-nAChR-containing synapses in SCG neurons Zaccaria et al, 2000;Del Signore et al, 2002). There are several possible explanations for this difference.…”

“…The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses. Best evidence for such a role comes from reports that full-length dystrophin regulates the stability of selective GABA A receptors and α3-containing nAChRs at a subset of central GABAergic and peripheral sympathetic nicotinic synapses (Knuesel et al, 1999(Knuesel et al, , 2001Zaccaria et al, 2000;Del Signore et al, 2002;Levi et al, 2002;Fritschy et al, 2003). However, our findings do not support a postsynaptic role for dystrophin and utrophin proteins at nicotinic synapses in parasympathetic CG neurons.…”

“…Precedence exists for different antibodies to utrophin giving contradictory results in neurons Knuesel et al, 2001). Interestingly, dystrophin was only detected at a subset (15%) of the nicotinic synapses in the SCG (Zaccaria et al, 2000). Moreover, dystrophin is also present at a subset of adherens junctions and in Schwann cells of the SCG .…”

“…Dystrophin colocalizes with selective GABA A receptor subunits at a subset of inhibitory GABAergic synapses in the CNS (Knuesel et al, 1999(Knuesel et al, , 2001Fritschy et al, 2003). Dystrophin also localizes to a subset of α3-nAChR-rich postsynaptic sites in sympathetic superior cervical ganglion (SCG) neurons Zaccaria et al, 2000;Del Signore et al, 2002). Although dystrophin is not required for cluster formation, there are decreases in the number of GABA A receptor and α3-containing nAChR clusters and impaired inhibitory synaptic transmission inmdx and dystrobrevin mutant mice Knuesel et al, 1999;Zaccaria et al, 2000;Del Signore et al, 2002;Anderson et al, 2003;Grady et al, 2006;Kueh et al, 2008).…”

Review: Dystroglycan in the Nervous System

“…The number of acetylcholine receptors and dystroglycan reactivity was found to be reduced in mdx mice that express a mutant dystrophin that cannot bind actin. Furthermore, the time-course of the decrease of intraganglionic synapses after axotomy was slowed in these mice, and the decrease of acetylcholine receptors, dystroglycan and dystrophin in relation to synapse number was totally abolished (Zaccaria et al, 2000). This suggests that the decrease seen in control wildtype mice is mediated by dystrophin and actin.…”