Normal photoresponses and alteredb-wave responses to APB in themdxCv3mouse isolated retina ERG supports role for dystrophin in synaptic transmission

112

Mutations in the human dystrophin gene cause the Duchenne and Becker muscular dystrophies. The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin has also been found to act as a scaffold for several signaling molecules, but the roles of dystrophin-mediated signaling pathways remain unknown. To further our understanding of this aspect of the function of dystrophin, we have generated Drosophila mutants that lack the large dystrophin isoforms and analyzed their role in synapse function at the neuromuscular junction. In expression and rescue studies, we show that lack of the large dystrophin isoforms in the postsynaptic muscle cell leads to elevated evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size, the size of the readily releasable vesicle pool as assessed with hypertonic shock, and the number of presynaptic neurotransmitter release sites (active zones) are not changed in the mutants. Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence of dystrophin results in increased probability of release. Absence of the large dystrophin isoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor function does not appear to be affected. Our results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis.

Section: Discussionmentioning

confidence: 99%

Dystrophin Is Required for Appropriate Retrograde Control of Neurotransmitter Release at theDrosophilaNeuromuscular Junction

Plas¹,

Pilgram²,

Plomp³

et al. 2006

112

“…This finding has been amply confirmed (for review, see Blake and Kroger, 2000;Anderson et al, 2002) and extended to include defects in the neural retina (Pillers et al, 1993) (for review, see Schmitz and Drenckhahn, 1997). Likewise, neural defects have been documented in dystrophin-deficient mutant mice, including behavioral and visual abnormalities and alterations in the structure and function of inhibitory cerebellar and retinal photoreceptor synapses Knuesel et al, 1999;Anderson et al, 2003;Green et al, 2004;Vaillend et al, 2004).…”

Section: Introductionmentioning

confidence: 89%

“…No retinal defects are apparent in mdx mice, reflecting the fact that the mutation in this allele does not prevent expression of Dp260 (D'Souza et al, 1995). However, other murine dystrophin mutants, in which Dp260 is missing (mdx 3cv ), do show defects in the ERG (D'Souza et al, 1995;Green et al, 2004).…”

Section: Location and Function Of Db In Retinamentioning

confidence: 99%

Cerebellar Synaptic Defects and Abnormal Motor Behavior in Mice Lacking α- and β-Dystrobrevin

Grady¹,

Wozniak²,

Ohlemiller³

et al. 2006

The dystrobrevins (␣DB and ␤DB) bind directly to dystrophin and are components of a transmembrane dystrophin-glycoprotein complex (DGC) that links the cytoskeleton to extracellular proteins in many tissues. We show here that ␣DB, ␤DB, and dystrophin are all concentrated at a discrete subset of inhibitory synapses on the somata and dendrites of cerebellar Purkinje cells. Dystrophin is depleted from these synapses in mice lacking both ␣DB and ␤DB, and DBs are depleted from these synapses in mice lacking dystrophin. In dystrophin mutants and ␣DB,␤DB double mutants, the size and number of GABA receptor clusters are decreased at cerebellar inhibitory synapses, and sensorimotor behaviors that reflect cerebellar function are perturbed. Synaptic and behavioral abnormalities are minimal in mice lacking either ␣DB or ␤DB. Together, our results show that the DGC is required for proper maturation and function of a subset of inhibitory synapses, that DB is a key component of this DGC, and that interference with this DGC leads to behavioral abnormalities. We suggest that motor deficits in muscular dystrophy patients, which are their cardinal symptoms, may reflect not only peripheral derangements but also CNS defects.

“…DL-2-Amino-4-phosphonobutyric acid (APB), an mGluR6 agonist, eliminates light-evoked ON bipolar cell depolarization and the associated b-wave of the flash electroretinogram (ERG) [mouse (Green et al, 2004); rabbit (Massey et al, 1983); salamander (Slaughter and Miller, 1981;Tian and Slaughter, 1995)]. APB has been reported to eliminate RGC spiking in response to light onset and has been used to dissect the putative contributions of the ON pathway to response properties of visual neurons in the lateral geniculate nucleus (LGN) and cortex (Schiller, 1982;Horton and Sherk, 1984).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic ON Responses of the Retinal OFF Pathway Are Suppressed by the ON Pathway

Renterı́a¹,

Tian²,

Cang³

et al. 2006

We show that these longer-latency ON responses are initiated in the OFF pathways. Our results expose a previously unrecognized intrinsic property of OFF retinal pathways that generates responses to light onset. In mGluR6-null mice, long-latency ON responses are observed in the visual cortex, indicating that they can be conducted reliably to higher visual areas. In wild-type (WT) mice, APB (DL-2-amino-4-phosphonobutyric acid), an mGluR6 agonist, blocks normal, short-latency ON responses but unmasks longer-latency ones. We find that these potentially confusing ON responses in the OFF pathway are actively suppressed in WT mice via two pharmacologically separable retinal circuits that are activated by the ON system in the retina. Consequently, we propose that a major function of the signaling of the ON pathway to the OFF pathway is suppression of these mistimed, and therefore inappropriate, light-evoked responses.