TY - JOUR
T1 - Cortico-hippocampal hyperexcitability in synapsin I/II/III knockout mice
T2 - Age-dependency and response to the antiepileptic drug levetiracetam
AU - Boido, D.
AU - Farisello, P.
AU - Cesca, F.
AU - Ferrea, E.
AU - Valtorta, F.
AU - Benfenati, F.
AU - Baldelli, P.
PY - 2010/11/24
Y1 - 2010/11/24
N2 - 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.
AB - 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.
KW - 4-aminopyridine
KW - Epilepsy
KW - Ictal discharge
KW - Interictal event
KW - Mouse model
KW - Multi-electrode arrays
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UR - http://www.scopus.com/inward/citedby.url?scp=77957862609&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2010.08.046
DO - 10.1016/j.neuroscience.2010.08.046
M3 - Article
C2 - 20804820
AN - SCOPUS:77957862609
VL - 171
SP - 268
EP - 283
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
IS - 1
ER -