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Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

ABSTRACT: Synapsin I (SynI) is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity by differentially affecting crucial steps of SV trafficking in excitatory and inhibitory synapses. SynI knockout (KO) mice are epileptic, and nonsense and missense mutations in the human SYN1 gene have a causal role in idiopathic epilepsy and autism. To get insights into the mechanisms of epileptogenesis linked to SYN1 mutations, we analyzed the effects of the recently identified Q555X mutation on neurotransmitter release dynamics and short-term plasticity (STP) in excitatory and inhibitory synapses. We used patch-clamp electrophysiology coupled to electron microscopy and multi-electrode arrays to dissect synaptic transmission of primary SynI KO hippocampal neurons in which the human wild-type and mutant SynI were expressed by lentiviral transduction. A parallel decrease in the SV readily releasable pool in inhibitory synapses and in the release probability in excitatory synapses caused a marked reduction in the evoked synchronous release. This effect was accompanied by an increase in asynchronous release that was much more intense in excitatory synapses and associated with an increased total charge transfer. Q555X-hSynI induced larger facilitation and post-tetanic potentiation in excitatory synapses and stronger depression after long trains in inhibitory synapses. These changes were associated with higher network excitability and firing/bursting activity. Our data indicate that imbalances in STP and release dynamics of inhibitory and excitatory synapses trigger network hyperexcitability potentially leading to epilepsy/autism manifestations.

SUBMITTER: Lignani G

PROVIDER: S-EPMC3652419 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

Lignani Gabriele G Raimondi Andrea A Ferrea Enrico E Rocchi Anna A Paonessa Francesco F Cesca Fabrizia F Orlando Marta M Tkatch Tatiana T Valtorta Flavia F Cossette Patrick P Baldelli Pietro P Benfenati Fabio F

Human molecular genetics 20130212 11

Synapsin I (SynI) is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity by differentially affecting crucial steps of SV trafficking in excitatory and inhibitory synapses. SynI knockout (KO) mice are epileptic, and nonsense and missense mutations in the human SYN1 gene have a causal role in idiopathic epilepsy and autism. To get insights into the mechanisms of epileptogenesis linked to SYN1 mutations, we analyzed the effects of the recently ident ...[more]

PMID: 23406870

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Project description:Functional magnetic resonance imaging (fMRI) studies have provided ample evidence for the involvement of the lateral occipital cortex (LO), fusiform gyrus (FG), and intraparietal sulcus (IPS) in visuo-haptic object integration. Here we applied 30 min of sham (non-effective) or real offline 1 Hz repetitive transcranial magnetic stimulation (rTMS) to perturb neural processing in left LO immediately before subjects performed a visuo-haptic delayed-match-to-sample task during fMRI. In this task, subjects had to match sample (S1) and target (S2) objects presented sequentially within or across vision and/or haptics in both directions (visual-haptic or haptic-visual) and decide whether or not S1 and S2 were the same objects. Real rTMS transiently decreased activity at the site of stimulation and remote regions such as the right LO and bilateral FG during haptic S1 processing. Without affecting behavior, the same stimulation gave rise to relative increases in activation during S2 processing in the right LO, left FG, bilateral IPS, and other regions previously associated with object recognition. Critically, the modality of S2 determined which regions were recruited after rTMS. Relative to sham rTMS, real rTMS induced increased activations during crossmodal congruent matching in the left FG for haptic S2 and the temporal pole for visual S2. In addition, we found stronger activations for incongruent than congruent matching in the right anterior parahippocampus and middle frontal gyrus for crossmodal matching of haptic S2 and in the left FG and bilateral IPS for unimodal matching of visual S2, only after real but not sham rTMS. The results imply that a focal perturbation of the left LO triggers modality-specific interactions between the stimulated left LO and other key regions of object processing possibly to maintain unimpaired object recognition. This suggests that visual and haptic processing engage partially distinct brain networks during visuo-haptic object matching.

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Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

Publications

Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

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