Regulation of transmitter release by Ca2+ and synaptotagmin: insights from a large CNS synapse

Kochubey, Olexiy; Lou, Xuelin; Schneggenburger, Ralf

doi:10.1016/j.tins.2011.02.006

Cited by 84 publications

(68 citation statements)

References 106 publications

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“…5,6 With respect to the SYT1 mutation, elements supporting its pathogenicity are the following: de novo origin; it has never been reported in control populations (dbSNPs, EVS and 1000genomes databases); non-synonymous variants across the whole gene are very rare in general population (only a single SNP with MAF slightly 41%); the substitution is predicted to be 'damaging' by the SIFT online tool (J. Craig Venter Institute, Rockville, MD, USA) and 'deleterious' with a probability of 0.75 by the PANTHER evolutionary analysis of coding SNPs (even though PolyPhen-2 prediction is 'benign'); it involves an important functional domain of SYT1; and SYT1 (synaptotagmin 1, OMIM: 185605) encodes a presynaptic protein, necessary for signal transmission across synapses. 11,12 The detected gene variants were submitted to LOVD database (http://databases.lovd.nl/shared/genes/MED13L). In particular, patient 1: individual id 00019865; patient 2: id 00019867; patient 3: id 00019868 and patient 4: id 00019920.…”

Section: Resultsmentioning

confidence: 99%

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

et al. 2015

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Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n =4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identiﬁed eight cases with ELP4. Additional Supporting Information may be found in the o deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identiﬁed with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a signiﬁcant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10\ud −3, as well as for autism, P =2.7× 10−3. Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range\ud of neurodevelopmental phenotypes from ASD to language impairment and epilepsy

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Section: Resultsmentioning

confidence: 99%

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

et al. 2015

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“…S5). Although not reflecting the true Ca 2+ concentration in an unperturbed presynaptic terminal, OGB-1 signals may provide information about possible distance-dependence of presynaptic Ca 2+ transients, which strongly influence the probability and time course of transmitter release (28) and consequently the amplitude and time course of the postsynaptic response (29). Neither the amplitude nor the decay time constant of OGB-1 fluorescence changes in presynaptic terminals varied with the distance from the PII soma, suggesting homogeneity of presynaptic release mechanisms (Fig.…”

Section: Composition Of Gaba a Receptor Subunits At Pii-gc Connectionsmentioning

confidence: 99%

Strength and duration of perisomatic GABAergic inhibition depend on distance between synaptically connected cells

Strüber

Jónás

Bartos

2015

Proc. Natl. Acad. Sci. U.S.A.

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GABAergic perisoma-inhibiting fast-spiking interneurons (PIIs) effectively control the activity of large neuron populations by their wide axonal arborizations. It is generally assumed that the output of one PII to its target cells is strong and rapid. Here, we show that, unexpectedly, both strength and time course of PII-mediated perisomatic inhibition change with distance between synaptically connected partners in the rodent hippocampus. Synaptic signals become weaker due to lower contact numbers and decay more slowly with distance, very likely resulting from changes in GABA A receptor subunit composition. When distance-dependent synaptic inhibition is introduced to a rhythmically active neuronal network model, randomly driven principal cell assemblies are strongly synchronized by the PIIs, leading to higher precision in principal cell spike times than in a network with uniform synaptic inhibition.interneurons | synaptic transmission | dentate gyrus | basket cell | gamma oscillations G ABAergic parvalbumin (PV)-expressing fast-spiking perisoma-inhibiting interneurons (PIIs) provide powerful synaptic inhibition to large numbers of target cells distributed over several hundred micrometers of cortical space (1-5). Extent and density of their axonal projection together with the perisomatic location of their output synapses close to the site of postsynaptic action potential generation are thought to provide tight control over the activity of target cells. Moreover, PIIs usually interact with other PIIs by reciprocal chemical and electrical synapses, thereby forming interneuron (IN) networks (4, 6, 7), which have been proposed to orchestrate the activity of cortical circuits. PIIs have been shown to receive rapid synaptic excitation (8) and to provide fast, strong, and faithful inhibitory signals to their postsynaptic partners (3,5,6). This fast and reliable signaling phenotype has been hypothesized to support the synchronization of neuronal networks leading to rhythmic activity patterns predominantly in the gamma frequency ranges [30-50 Hz, low gamma; 50-90 Hz, midfrequency gamma; 90-150 Hz, high gamma (7, 9)]. Several lines of evidence indeed indicate that PIIs are critical for the emergence of gamma activity. PIIs discharge at high frequencies tightly phase-locked to gamma cycles in vivo (10-13), they can entrain the activity of large principal cell assemblies (2, 14, 15), and silencing them impairs cortical gamma oscillations (14, 16). Thus, fast-spiking PIIs are generally regarded as a reliably active IN type that paces activity of large principal cell populations by strong and fast uniform inhibition.However, uniformity of PII output signaling has only been assumed and never been tested experimentally. In fact, quantitative analysis of the PII axon morphology shows a gradual decline in axon collateral density with distance from the soma (17-19) frequently interpreted as a reduction in connection probability at larger distances (20, 21), comparable to observations from excitatory glutamatergic neurons in the neo...

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“…SV2C has a much more restricted distribution being found mostly in the basal ganglia, midbrain, and brainstem (2).The most studied isoform, SV2A, has been shown to regulate the expression and trafficking of the synaptic vesicle calcium sensor protein, synaptotagmin (4). Synaptotagmin is required for the calcium-mediated exocytosis of neurotransmitters stored in synaptic vesicles (5). SV2A also plays a synaptotagmin-independent role in neurotransmitter release, most likely functioning in a maturation step of primed synaptic vesicles that converts the vesicles into a Ca 2ϩ -and synaptotagmin-responsive state (6).…”

Section: Synaptic Vesicle Protein 2 (Sv2)mentioning

confidence: 99%

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

Madeo

Kovács

Pearce

2014

Journal of Biological Chemistry

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Regulation of transmitter release by Ca2+ and synaptotagmin: insights from a large CNS synapse

Cited by 84 publications

References 106 publications

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

Strength and duration of perisomatic GABAergic inhibition depend on distance between synaptically connected cells

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

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