title: Synaptic and extrasynaptic origin of the excitation/inhibition imbalance in the hippocampus of synapsin I/II/III knockout mice.
abstract: Synapsins (Syn I, Syn II, and Syn III) are a family of synaptic vesicle phosphoproteins regulating synaptic transmission and plasticity. SYN1/2 genes have been identified as major epilepsy susceptibility genes in humans and synapsin I/II/III triple knockout (TKO) mice are epileptic. However, excitatory and inhibitory synaptic transmission and short-term plasticity have never been analyzed in intact neuronal circuits of TKO mice. To clarify the generation and expression of the epileptic phenotype, we performed patch-clamp recordings in the CA1 region of acute hippocampal slices from 1-month-old presymptomatic and 6-month-old epileptic TKO mice and age-matched controls. We found a strong imbalance between basal glutamatergic and γ-aminobutyric acid (GABA)ergic transmission with increased evoked excitatory postsynaptic current and impaired evoked inhibitory postsynaptic current amplitude. This imbalance was accompanied by a parallel derangement of short-term plasticity paradigms, with enhanced facilitation of glutamatergic transmission in the presymptomatic phase and milder depression of inhibitory synapses in the symptomatic phase. Interestingly, a lower tonic GABA(A) current due to the impaired GABA release is responsible for the more depolarized resting potential found in TKO CA1 neurons, which makes them more susceptible to fire. All these changes preceded the appearance of epilepsy, indicating that the distinct changes in excitatory and inhibitory transmission due to the absence of Syns initiate the epileptogenic process.
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, 16163 Genova, Italy. fabio.benfenati@iit.it
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Farisello
authors.forename: Davide
authors.initials: D
authors.lastname: Boido
authors.forename: Thierry
authors.initials: T
authors.lastname: Nieus
authors.forename: Lucian
authors.initials: L
authors.lastname: Medrihan
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Cesca
authors.forename: Flavia
authors.initials: F
authors.lastname: Valtorta
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008962:Models, Theoretical; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D013569:Synapses / Q000502:physiology; D016704:Synapsins / Q000172:deficiency / Q000235:genetics; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D016704:Synapsins