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Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections.

ABSTRACT: Fic domains can catalyze the addition of adenosine monophosphate to target proteins. To date, the function of Fic domain proteins in eukaryotic physiology remains unknown. We generated genetic models of the single Drosophila Fic domain–containing protein, Fic. Flies lacking Fic were viable and fertile, but blind. Photoreceptor cells depolarized normally following light stimulation, but failed to activate postsynaptic neurons, as indicated by the loss of ON transients in electroretinograms, consistent with a neurotransmission defect. Functional rescue of neurotransmission required expression of enzymatically active Fic on capitate projections of glia cells, but not neurons, supporting a role in the recycling of the visual neurotransmitter histamine. Histamine levels were reduced in the lamina of Fic null flies, and dietary histamine partially restored ON transients. These findings establish a previously unknown regulatory mechanism in visual neurotransmission and provide, to the best of our knowledge, the first evidence for a role of glial capitate projections in neurotransmitter recycling.

SUBMITTER: Rahman M

PROVIDER: S-EPMC3578554 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections.

Rahman Mokhlasur M Ham Hyeilin H Liu Xinran X Sugiura Yoshie Y Orth Kim K Krämer Helmut H

Nature neuroscience 20120601 6

Fic domains can catalyze the addition of adenosine monophosphate to target proteins. To date, the function of Fic domain proteins in eukaryotic physiology remains unknown. We generated genetic models of the single Drosophila Fic domain–containing protein, Fic. Flies lacking Fic were viable and fertile, but blind. Photoreceptor cells depolarized normally following light stimulation, but failed to activate postsynaptic neurons, as indicated by the loss of ON transients in electroretinograms, consi ...[more]

PMID: 22544313

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Project description:Changes in UBE3A expression levels in neurons can cause neurogenetic disorders ranging from Angelman syndrome (AS) (decreased levels) to autism (increased levels). Here we investigated the effects on neuronal function of varying UBE3A levels using the Drosophila neuromuscular junction as a model for both of these neurogenetic disorders. Stimulations that evoked excitatory junction potentials (EJPs) at 1 Hz intermittently failed to evoke EJPs at 15 Hz in a significantly higher proportion of Dube3a over-expressors using the pan neuronal GAL4 driver C155-GAL4 (C155-GAL4>UAS-Dube3a) relative to controls (C155>+ alone). However, in the Dube3a over-expressing larval neurons with no failures, there was no difference in EJP amplitude at the beginning of the train, or the rate of decrease in EJP amplitude over the course of the train compared to controls. In the absence of tetrodotoxin (TTX), spontaneous EJPs were observed in significantly more C155-GAL4>UAS-Dube3a larva compared to controls. In the presence of TTX, spontaneous and evoked EJPs were completely blocked and mEJP amplitude and frequency did not differ among genotypes. These data suggest that over-expression of wild type Dube3a, but not a ubiquitination defective Dube3a-C/A protein, compromises the ability of motor neuron axons to support closely spaced trains of action potentials, while at the same time increasing excitability. EJPs evoked at 15 Hz in the absence of Dube3a (Dube3a(15b) homozygous mutant larvae) decayed more rapidly over the course of 30 stimulations compared to w(1118) controls, and Dube3a(15b) larval muscles had significantly more negative resting membrane potentials (RMP). However, these results could not be recapitulated using RNAi knockdown of Dube3a in muscle or neurons alone, suggesting more global developmental defects contribute to this phenotype. These data suggest that reduced UBE3A expression levels may cause global changes that affect RMP and neurotransmitter release from motorneurons at the neuromuscular junction. Similar affects of under- and over-expression of UBE3A on membrane potential and synaptic transmission may underlie the synaptic plasticity defects observed in both AS and autism.

Dataset Information

Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections.

Publications

Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections.

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