Memory, Synapse Stability, and β-Adducin

In this issue of Neuron, two studies by Pielage et al. and Bednarek and Caroni suggest that the cytoskeleton regulator β-Adducin provides an activity-dependent switch controlling synapse disassembly and assembly at the Drosophila neuromuscular junction (NMJ) and the mouse hippocampus. In mice, the β-Adducin switch is required for the improvement of learning and memory induced by enriched environments

Synaptic Homeostasis on the Fast Track

Synaptic homeostasis is a phenomenon that prevents the nervous system from descending into chaos. In this issue of Neuron, Frank et al. overturn the notion that synaptic homeostasis at Drosophila NMJs is a slow developmental process. They report that postsynaptic changes are offset within minutes by a homeostatic increase in neurotransmitter release that requires the presynaptic Ca2+ channel Cacophony

A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.National Institute of Neurological Disorders and StrokeUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS083849, R21NS094809]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Drosophila Hsc70-4 Is Critical for Neurotransmitter Exocytosis In Vivo

AbstractPrevious in vitro studies of cysteine-string protein (CSP) imply a potential role for the clathrin-uncoating ATPase Hsc70 in exocytosis. We show that hypomorphic mutations in Drosophila Hsc70-4 (Hsc4) impair nerve-evoked neurotransmitter release, but not synaptic vesicle recycling in vivo. The loss of release can be restored by increasing external or internal Ca2+ and is caused by a reduced Ca2+ sensitivity of exocytosis downstream of Ca2+ entry. Hsc4 and CSP are likely to act in common pathways, as indicated by their in vitro protein interaction, the similar loss of evoked release in individual and double mutants, and genetic interactions causing a loss of release in trans-heterozygous hsc4-csp double mutants. We suggest that Hsc4 and CSP cooperatively augment the probability of release by increasing the Ca2+ sensitivity of vesicle fusion

Ferrying Wingless across the Synaptic Cleft

Secreted Wnt morphogens mediate cell-cell communication, but the mechanism of Wnt transfer between cells is unknown. Korkut et al. (2009) report that the transmembrane protein Evi is a versatile carrier that guides Wingless to presynaptic terminals of motor neurons and then escorts it across the synaptic cleft. In postsynaptic muscles, Evi promotes Frizzled-2 trafficking

Paralysis and Early Death in Cysteine String Protein Mutants of Drosophila

Multimeric complexes of synaptic vesicle and terminal membrane proteins are important components of the neurotransmitter release mechanism. The csp gene of Drosophila encodes proteins homologous to synaptic vesicle proteins in Torpedo. Monoclonal antibodies demonstrate different distributions of isoforms at distinct subsets of terminals. Deletion of the csp gene in Drosophila causes a temperature-sensitive block of synaptic transmission, followed by paralysis and premature death

Presynaptic dysfunction in drosophila csp mutants

Cysteine string proteins are synapse-specific proteins. In Drosophila, csp deletion mutants exhibit temperature-sensitive paralysis and early death. Here, we report that neuromuscular transmission is impaired presynaptically in these csp mutant larvae. At 22°C, evoked transmitter release is depressed relative to wild type and rescued controls, and high frequency stimulation of the nerve leads to sporadic failures. At 30°C, stimulus-evoked responses decline gradually before failing completely. When the temperature is returned to 22°C, evoked responses recover. Spontaneous release events persist at both 22°C and 30°C. Since nerve conduction and postsynaptic sensitivity are unaffected, these data indicate that csp mutations disrupt depolarization-secretion coupling. This disruption explains the cellular basis of the temperature-sensitive paralysis of these organisms

Presynaptic dysfunction in drosophila csp mutants

Cysteine string proteins are synapse-specific proteins. In Drosophila, csp deletion mutants exhibit temperature-sensitive paralysis and early death. Here, we report that neuromuscular transmission is impaired presynaptically in these csp mutant larvae. At 22°C, evoked transmitter release is depressed relative to wild type and rescued controls, and high frequency stimulation of the nerve leads to sporadic failures. At 30°C, stimulus-evoked responses decline gradually before failing completely. When the temperature is returned to 22°C, evoked responses recover. Spontaneous release events persist at both 22°C and 30°C. Since nerve conduction and postsynaptic sensitivity are unaffected, these data indicate that csp mutations disrupt depolarization-secretion coupling. This disruption explains the cellular basis of the temperature-sensitive paralysis of these organisms