Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy

Garcia, CC; Blair, H.J.; Seager, Matthew A.; Coulthard, Alan; Tennant, Sharon M.; Buddles, M; Curtis, A; Goodship, Judith A.

doi:10.1136/jmg.2003.013680

Cited by 190 publications

(179 citation statements)

References 17 publications

(8 reference statements)

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“…A severe epileptic phenotype was found in genetically altered mice lacking members of the Syn (for review, see Baldelli et al, 2006) and SV2 (Crowder et al, 1999;Janz et al, 1999;Custer et al, 2006) families, whereas epilepsy was not observed in mouse mutants deleted for other SV or presynaptic plasma membrane proteins. Interestingly, a new form of familial X-linked epilepsy characterized by a nonsense mutation in the SYN1 gene was recently reported (Garcia et al, 2004), making SynI KO mice the only experimental model of human epilepsy associated with SV defects. Epileptic seizures are generated by an initially localized hyperexcitability that spreads into a series of interconnected neuronal networks, where it might not be properly counterbalanced and circumscribed by inhibitory mechanisms (Steinlein, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic deletion of single or multiple SYN genes (with the notable exception of SYN3) (Feng et al, 2002) produces a severe epileptic phenotype characterized by partial, secondarily generalized seizures that appear after 2-3 months of age and become progressively more intense (Rosahl et al, 1995;Gitler et al, 2004). Interestingly, a familial X-linked epilepsy has been recently reported to be associated with a nonsense mutation in the human SYN1 gene (Garcia et al, 2004). The epileptic phenotype suggests that SynI has a role in the control of the excitability of cortical networks.…”

Section: Introductionmentioning

confidence: 99%

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Lack of Synapsin I Reduces the Readily Releasable Pool of Synaptic Vesicles at Central Inhibitory Synapses

et al. 2007

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Synapsins (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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lack of Synapsin I Reduces the Readily Releasable Pool of Synaptic Vesicles at Central Inhibitory Synapses

et al. 2007

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“…Indeed, synapsin I knock-out mice exhibit spontaneous seizures , and mutations in the synapsin I gene have been reported recently to cause epilepsy and/or mental retardation in humans (Garcia et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

Bonanomi¹,

Menegon²,

Miccio³

et al. 2005

J. Neurosci.

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In developing neurons, synaptic vesicles (SVs) undergo cycles of exo-endocytosis along isolated axons. However, it is currently unknown whether SV exocytosis is regulated before synaptogenesis. Here, we show that cAMP-dependent pathways affect SV distribution and recycling in the axonal growth cone and that these effects are mediated by the SV-associated phosphoprotein synapsin I. The presence of synapsin I on SVs is necessary for the correct localization of the vesicles in the central portion of the growth cone. Phosphorylation of synapsin I by cAMP-dependent protein kinase (protein kinase A) causes the dissociation of the protein from the SV membrane, allowing diffusion of the vesicles to the periphery of the growth cone and enhancing their rate of recycling. These results provide new clues as to the bases of the well known activity of synapsin I in synapse maturation and indicate that molecular mechanisms similar to those operating at mature nerve terminals are active in developing neurons to regulate the SV life cycle before synaptogenesis.

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“…The importance of characterizing the excitable phenotype developed by Syn deficiencies is highlighted by the fact that Syn deletion and mutations have been associated with the development of epileptic phenotypes in animals (Li et al, 1995;Rosahl et al, 1995;Gitler et al, 2004;Etholm and Heggelund, 2009;Ketzef et al, 2011;Etholm et al, 2013;Ketzef and Gitler, 2014). In humans, epilepsy and other disorders have been linked to mutations in SynI (Garcia et al, 2004;Fassio et al, 2011b;Lignani et al, 2013;Giannandrea et al, 2013) and SynII genes (Cavalleri et al, 2007;Lakhan et al, 2010;Corradi et al, 2014). In addition, the seizure susceptibility of mice TKO brain slices has been reported to anticipate epileptic phenotypes (Boido et al, 2010;Feliciano et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Subconvulsant doses of pentylenetetrazol uncover the epileptic phenotype of cultured synapsin-deficient Helix serotonergic neurons in the absence of excitatory and inhibitory inputs

Brenes

Carabelli²,

Gosso³

et al. 2016

Epilepsy Research

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Synapsins are a family of presynaptic proteins related to several processes of synaptic functioning. A variety of reports have linked mutations in synapsin genes with the development of epilepsy. Among the proposed mechanisms, a main one is based on the synapsin-mediated imbalance towards network hyperexcitability due to differential effects on neurotransmitter release in GABAergic and glutamatergic synapses. Along this line, a non-synaptic effect of synapsin depletion increasing neuronal excitability has recently been described in Helix neurons. To further investigate this issue, we examined the effect of synapsin knock-down on the development of pentylenetetrazol (PTZ)-induced epileptic-like activity using single neurons or isolated monosynaptic circuits reconstructed on microelectrode arrays (MEAs). Compared to control neurons, synapsin-silenced neurons showed a lower threshold for the development of epileptic-like activity and prolonged periods of activity, together with the occurrence of spontaneous firing after recurrent PTZ-induced epileptic-like activity. These findings highlight the crucial role of synapsin on neuronal excitability regulation in the absence of inhibitory or excitatory inputs. KeywordsSynapsin; pentylenetetrazol (PTZ); invertebrate neurons; convulsants; Helix snail. Highlights• Synapsin-silenced cells lacking synaptic inputs exhibit greater PTZ susceptibility.• PTZ-induced epileptic-like behaviors were increased in synapsin-silenced cells.• Recurrent epileptic-like activity impairs control neuron synaptogenesis.• Recurrent epileptic-like activity is associated with spontaneous spiking activity.

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Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy

Cited by 190 publications

References 17 publications

Lack of Synapsin I Reduces the Readily Releasable Pool of Synaptic Vesicles at Central Inhibitory Synapses

Lack of Synapsin I Reduces the Readily Releasable Pool of Synaptic Vesicles at Central Inhibitory Synapses

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

Subconvulsant doses of pentylenetetrazol uncover the epileptic phenotype of cultured synapsin-deficient Helix serotonergic neurons in the absence of excitatory and inhibitory inputs

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