Synapsins (SynI, SynII, SynIII) are a multigene family of synaptic vesicle 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 hyperexcitability and epileptiform activity induced by 4-aminopyridine (4AP) in acute slices from presymptomatic (3-weeks-old) and epileptic (1-year-old) SynI/II/III triple knockout (TKO) mice and aged-matched triple wild type (TWT) controls and assessed the effect of the synaptic vesicle-targeted antiepileptic drug levetiracetam (LEV) in reverting the epileptic phenotype. Both fast and slow interictal (I-IC) activity and ictal (IC) seizures were observed in both genotypes. The incidence of fast I-IC 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 ameliorated 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 synaptic vesicle protein acting as LEV receptor, in cortex and hippocampus. The results demonstrate that deletion of synapsin 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 hyperexcitability by enhancing the inhibition/excitation ratio, although the effect is hindered in TKO slices due to the concomitant decrease of its receptor SV2A.
Cortico-hippocampal hyperexcitability in synapsin I/II/III knockout mice: age-dependency and response to the antiepileptic drug levetiracetam.
VALTORTA , FLAVIA;
2010-01-01
Abstract
Synapsins (SynI, SynII, SynIII) are a multigene family of synaptic vesicle 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 hyperexcitability and epileptiform activity induced by 4-aminopyridine (4AP) in acute slices from presymptomatic (3-weeks-old) and epileptic (1-year-old) SynI/II/III triple knockout (TKO) mice and aged-matched triple wild type (TWT) controls and assessed the effect of the synaptic vesicle-targeted antiepileptic drug levetiracetam (LEV) in reverting the epileptic phenotype. Both fast and slow interictal (I-IC) activity and ictal (IC) seizures were observed in both genotypes. The incidence of fast I-IC 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 ameliorated 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 synaptic vesicle protein acting as LEV receptor, in cortex and hippocampus. The results demonstrate that deletion of synapsin 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 hyperexcitability by enhancing the inhibition/excitation ratio, although the effect is hindered in TKO slices due to the concomitant decrease of its receptor SV2A.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
