Cortico-hippocampal hyperexcitability in synapsin I/II/III knockout mice: age-dependency and response to the antiepileptic drug levetiracetam

• Published in: Neuroscience Vol. 171; no. 1; pp. 268 - 283
• Main Authors: Boido, D, Farisello, P, Cesca, F, Ferrea, E, Valtorta, F, Benfenati, F, Baldelli, P
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 24.11.2010; Elsevier
• Subjects: 4-aminopyridine; 4-Aminopyridine - pharmacology; Age; Aging; Analysis of Variance; Animals; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Disease Models, Animal; Drug Interactions; Electrodes; epilepsy; Epilepsy, Tonic-Clonic - genetics; Epilepsy, Tonic-Clonic - pathology; Evoked Potentials - drug effects; Evoked Potentials - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Hippocampus - pathology; Hippocampus - physiopathology; ictal discharge; In Vitro Techniques; interictal event; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; mouse model; multi-electrode arrays; Nerve Tissue Proteins - metabolism; Neurology; Neurons - drug effects; Neuropharmacology; Patch-Clamp Techniques; Pharmacology. Drug treatments; Piracetam - analogs & derivatives; Piracetam - pharmacology; Potassium Channel Blockers - pharmacology; Synapsins - deficiency; Synaptophysin - metabolism; Vertebrates: nervous system and sense organs; epilepsy; power spectral density; antiepileptic drug; interictal; MEAs; synaptic vesicle; interictal event; ictal discharge; 4-aminopyridine; triple wild type; multi-electrode arrays; IC; BMI; AED; knockout; PSD; 4AP; SV; mouse model; KO; synapsin triple knockout; microelectrode arrays; Syn; ACSF; bicuculline methiodide; CGP; artificial cerebrospinal fluid; TWT; ictal; CGP55485; synapsin; TKO; LEV; I-IC; levetiracetam; Synapsin I; Animal model; Nervous system diseases; Epilepsy; Rodentia; Central nervous system; Anticonvulsant; Encephalon; Cerebral disorder; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Hyperexcitability; Mutation; Age; Hippocampus; Levetiracetam
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.08.046

Abstract Synapsins (SynI, SynII, SynIII) are a multigene family of synaptic vesicle (SV) phosphoproteins implicated in the regulation of synaptic transmission and plasticity. Synapsin I, II, I/II and I/II/III knockout mice are epileptic and SYN1/2 genes have been identified as major epilepsy susceptibility genes in humans. We analyzed cortico-hippocampal epileptiform activity induced by 4-aminopyridine (4AP) in acute slices from presymptomatic (3-weeks-old) and symptomatic (1-year-old) Syn I/II/III triple knockout (TKO) mice and aged-matched triple wild type (TWT) controls and assessed the effect of the SV-targeted antiepileptic drug (AED) levetiracetam (LEV) in reverting the epileptic phenotype. Both fast and slow interictal (I-IC) and ictal (IC) events were observed in both genotypes. The incidence of fast I-IC events was higher in presymptomatic TKO slices, while frequency and latency of I-IC events were similar in both genotypes. The major age and genotype effects were observed in IC activity, that was much more pronounced in 3-weeks-old TKO and persisted with age, while it disappeared from 1-year-old TWT slices. LEV virtually suppressed fast I-IC and IC discharges from 3-weeks-old TWT slices, while it only increased the latency of fast I-IC and IC activity in TKO slices. Analysis of I-IC events in patch-clamped CA1 pyramidal neurons revealed that LEV increased the inhibitory/excitatory ratio of I-IC activity in both genotypes. The lower LEV potency in TKO slices of both ages was associated with a decreased expression of SV2A, a SV protein acting as LEV receptor, in cortex and hippocampus. The results demonstrate that deletion of Syn genes is associated with a higher propensity to 4AP-induced epileptic paroxysms that precedes the onset of epilepsy and consolidates with age. LEV ameliorates such hyper excitability by enhancing the inhibition/excitation ratio, although the effect is hindered in TKO slices which exhibit a concomitant decrease in the levels of the LEV receptor SV2A.