1,721,034 research outputs found
Formation, isomerization and reduction of disulphide bonds during protein quality control in the endoplasmic reticulum.
No full textGABA induces norepinephrine exocytosis from hippocampal noradrenergic axon terminals by a dual mechanism involving different voltage-sensitive calcium channels
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Synaptic genes and neurodevelopmental disorders: From molecular mechanisms to developmental strategies of behavioral testing
No full textSynaptopathies are a class of neurodevelopmental disorders caused by modification in genes coding for synaptic proteins. These proteins oversee the process of neurotransmission, mainly controlling the fusion and recycling of synaptic vesicles at the presynaptic terminal, the expression and localization of receptors at the postsynapse and the coupling between the pre-and the postsynaptic compartments. Murine models, with homozygous or het-erozygous deletion for several synaptic genes or knock-in for specific pathogenic mutations, have been devel-oped. They have proved to be extremely informative for understanding synaptic physiology, as well as for clarifying the patho-mechanisms leading to developmental delay, epilepsy and motor, cognitive and social im-pairments that are the most common clinical manifestations of neurodevelopmental disorders. However, the onset of these disorders emerges during infancy and adolescence while the behavioral phenotyping is often conducted in adult mice, missing important information about the impact of synaptic development and matu-ration on the manifestation of the behavioral phenotype. Here, we review the main achievements obtained by behavioral testing in murine models of synaptopathies and propose a battery of behavioral tests to improve classification, diagnosis and efficacy of potential therapeutic treatments. Our aim is to underlie the importance of studying behavioral development and better focusing on disease onset and phenotypes
Lack of synapsin I reduces the readily releasable pool of synaptic vesicles at central inhibitory synapses
No full textSynapsins (Syns) are synaptic vesicle (SV) phosphoproteins that play a role in neurotransmitter release and synaptic plasticity by acting
at multiple steps of exocytosis. Mutation of SYN genes results in an epileptic phenotype in mouse and man suggesting a role of Syns in the
control of network excitability. We have studied the effects of the genetic ablation of the SYN1 gene on inhibitory synaptic transmission
in primary hippocampal neurons. Inhibitory neurons lacking SynI showed reduced amplitude of IPSCs evoked by isolated action potentials.
The impairment in inhibitory transmission was caused by a decrease in the size of the SV readily releasable pool, rather than by
changes in release probability or quantal size. The reduction of the readily releasable pool was caused by a decrease in the number of SVs
released by single synaptic boutons in response to the action potential, in the absence of variations in the number of synaptic contacts
between couples of monosynaptically connected neurons. The deletion of SYN1 did not affect paired-pulse depression or post-tetanic
potentation, but was associated with a moderate increase of synaptic depression evoked by trains of action potentials, which became
apparent at high stimulation frequencies and was accompanied by a slow down of recovery from depression. The decreased size of the SV
readily releasable pool, coupled with a decreased SV recycling rate and refilling by the SV reserve pool, may contribute to the epileptic
phenotype of SynI knock-out mice
Entrapping of impermeant probes of different size into nonpermeabilized synaptosomes as a method to study presynaptic mechanisms
No full textThe sensisivity of catecholamine release to botulinum toxin C 1 and E suggests selective targeting of vesicles set into the readily releasable pool
No full textThe impact of syntaxin and SNAP‐25 cleavage on [3H]noradrenaline ([3H]NA) and [3H]dopamine ([3H]DA) exocytotic release evoked by different stimuli was studied in superfused rat synaptosomes. The external Ca2+‐dependent K+‐induced [3H]catecholamine overflows were almost totally abolished by botulinum toxin C1 (BoNT/C1), which hydrolyses syntaxin and SNAP‐25, or by botulinum toxin E (BoNT/E), selective for SNAP‐25. BoNT/C1 cleaved 25% of total syntaxin and 40% of SNAP‐25; BoNT/E cleaved 40% of SNAP‐25 but left syntaxin intact. The GABA uptake‐induced releases of [3H]NA and [3H]DA were differentially affected: both toxins blocked the former, dependent on external Ca2+, but not the latter, internal Ca2+‐dependent. BoNT/C1 or BoNT/E only slightly reduced the ionomycin‐evoked [3H]catecholamine release. More precisely, [3H]NA exocytosis induced by ionomycin was sensitive to toxins in the early phase of release but not later. The Ca2+‐independent [3H]NA exocytosis evoked by hypertonic sucrose, thought to release from the readily releasable pool (RRP) of vesicles, was significantly reduced by BoNT/C1. Pre‐treating synaptosomes with phorbol‐12‐myristate‐13‐acetate, to increase the RRP, enhanced the sensitivity to BoNT/C1 of [3H]NA release elicited by sucrose or ionomycin. Accordingly, cleavage of syntaxin was augmented by the phorbol‐ester. To conclude, our results suggest that clostridial toxins selectively target exocytosis involving vesicles set into the RRP
CGP 52432: a novel potent and selective GABAB autoreceptor antagonist in rat cerebral cortex.
No full textEvidence for calcium-dependent vesicular transmitter release insensitive to tetanus toxin and botulinum toxin type F
No full textCharacterisation of the GABA autoreceptor in human neocortex as a pharmacological subtype of the GABAB receptor
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