title: 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.
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genova 16163, Italy.
authors: Gabriele
authors: G
authors: Lignani
authors: Andrea
authors: A
authors: Raimondi
authors: Enrico
authors: E
authors: Ferrea
authors: Anna
authors: A
authors: Rocchi
authors: Francesco
authors: F
authors: Paonessa
authors: Fabrizia
authors: F
authors: Cesca
authors: Marta
authors: M
authors: Orlando
authors: Tatiana
authors: T
authors: Tkatch
authors: Flavia
authors: F
authors: Valtorta
authors: Patrick
authors: P
authors: Cossette
authors: Pietro
authors: P
authors: Baldelli
authors: Fabio
authors: F
authors: Benfenati
mesh_terms: D000818:Animals; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D055503:Protein Multimerization; D021381:Protein Transport; D013569:Synapses / Q000378:metabolism*; D016704:Synapsins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D055366:Synaptic Potentials; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D016704:Synapsins