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.
Original language | English (US) |
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Pages (from-to) | 2186-2199 |
Number of pages | 14 |
Journal | Human molecular genetics |
Volume | 22 |
Issue number | 11 |
DOIs | |
State | Published - Jun 2013 |
Funding
This work was supported by research grants from the Italian Ministry of University and Research (PRIN to P.B. and F.B.), the Italian Ministry of Health Progetto Giovani (to P.B.), the Compagnia di San Paolo, Torino (to P.B. and F.B.) and the Quebec Ministry of International Relationships and Italian Ministry of Foreign Affairs (to P.C. and F.B.). The support of Telethon-Italy (Grant GGP09066 to P.B., GGP09134 to F.B. and F.V.) and European Union’s FP7/ 2007-2013 grant “FOCUS” are also acknowledged. Funding to pay the Open Access publication charges for this article was provided by Telethon - Italy.
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
- Molecular Biology