Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperCortico-hippocampal hyperexcitability in synapsin I/II/III knockout mice: age-dependency and response to the antiepileptic drug levetiracetam
Section snippets
Experimental animals
Homozygous Syn TKO mice (Gitler et al., 2004) were kindly provided by Drs. H.T. Kao (Brown University, Providence, RI, USA) and Paul Greengard (The Rockefeller University, NY, USA). TKO mice were rederived on a C57BL/6J background (Charles River, Calco, Italy) obtaining single and multiple Syn KO strains up to TKO and matching TWT mice. For genotyping, tail DNA was extracted and analyzed by PCR using the previously described primers (Gitler et al., 2004). Mice were housed (2–4 per cage) under
Ontogeny of epilepsy in TKO mice
Deletion of SynI, SynII, SynI/II or SynI/II/III (TKO) gives rise to an epileptic phenotype that is not present at birth and develops with age (Li et al., 1995, Rosahl et al., 1995, Gitler et al., 2004, Corradi et al., 2008, Etholm and Heggelund, 2009). Similar to the other strains, TKO mice did not show either spontaneous or stimuli-evoked seizures until 8–9 weeks of age. After this time, mice started to suffer of generalized tonic-clonic attacks which persisted in the adulthood: although
Discussion
Genetically-engineered mouse lines have provided a number of valuable epilepsy models with the potential to link epileptogenesis to changes in both specific genes and neuronal function (Noebels, 2003). The genetic deletion of the Syns in mice is of particular interest in this respect, because it represents the first model of epilepsy based on concomitant alterations of the release of excitatory and inhibitory neurotransmitters and because of the widespread distribution of these SV proteins in
Acknowledgments
We thank drs. Paul Greengard (The Rockefeller University, New York, NY) and Hung-Teh Kao (Brown University, Providence, RI) for providing us with the TKO mutant mouse strain and for invaluable discussions and Giacomo Gaggero for technical help. This study was supported by research grants from the Italian Ministry of University and Research (PRIN to FB and PB), the Italian Ministry of Health Progetto Giovani (to PB), the Compagnia di San Paolo, Torino (to FB, FV and PB), UCB SA Brussels-Belgium
References (47)
- et al.
Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro
Prog Neurobiol
(2002) - et al.
Synapsin-dependent development of glutamatergic synaptic vesicles and presynaptic plasticity in postnatal mouse brain
Neuroscience
(2009) - et al.
Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study
Lancet Neurol 6
(2007) - et al.
The synapsins: key actors of synapse function and plasticity
Prog Neurobiol
(2010) - et al.
Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies
Neuron
(2003) - et al.
Seizure elements and seizure element transitions during tonic-clonic seizure activity in the synapsin I/II double knockout mouse: a neuroethological description
Epilepsy Behav
(2009) - et al.
Tetraethylammonium-induced epileptiform activity in young and adult rat hippocampus
Brain Res Dev Brain Res
(1993) - et al.
SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release
Neuron
(1999) - et al.
Visualization of SV2A conformations in situ by the use of protein tomography
Biochem Biophys Res Commun
(2008) - et al.
Seizure disorders in mutant miceRelevance to human epilepsies
Curr Opin Neurobiol
(1999)
Molecular anatomy of a trafficking organelle
Cell
Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro
J Neurosci
Differential expression of synaptic vesicle protein 2 (SV2) isoforms
J Neurosci
Lack of synapsin I reduces the readily releasable pool of synaptic vesicles at central inhibitory synapses
J Neurosci
CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures
J Neurosci
CA3-released entorhinal seizures disclose dentate gyrus epileptogenicity and unmask a temporoammonic pathway
J Neurophysiol
Patch-clamp recording from mossy fiber terminals in hippocampal slices
Nat Protoc
SV2 renders primed synaptic vesicles competent for Ca2+-induced exocytosis
J Neurosci
Synapsin dispersion and reclustering during synaptic activity
Nat Neurosci
Opposite changes in glutamatergic and GABAergic transmission underlie the diffuse hyperexcitability of synapsin I-deficient cortical networks
Cereb Cortex
Synapsin-I- and synapsin-II-null mice display an increased age-dependent cognitive impairment
J Cell Sci
Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A)
Proc Natl Acad Sci U S A
Synaptic vesicle protein 2 enhances release probability at quiescent synapses
J Neurosci
Cited by (53)
An updated reappraisal of synapsins: structure, function and role in neurological and psychiatric disorders
2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :By analyzing cortico-hippocampal epileptiform activity induced by 4-aminopyridine (4AP) in acute slices from pre-symptomatic (3-weeks-old) and symptomatic (1-year-old) Tko mice and aged matched controls, Boido and coauthors (Boido et al., 2010) found that the incidence of fast interictal events is higher in pre-symptomatic Tko slices. This notwithstanding, the frequency and latency of inter ictal events are similar in both genotypes (Boido et al., 2010). They also reported that the lower potency of levetiracetam in Tko slices is associated with a decreased expression of SV2A, a SVs-associated protein acting as levetiracetam receptor (Lynch et al., 2004).
Dysfunction of the serotonergic system in the brain of synapsin triple knockout mice is associated with behavioral abnormalities resembling synapsin-related human pathologies
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Indeed, the significant reduction in the duration of immobility in TKO mice compared with WT is likely the result of the hyperactivity of mutant mice rather than a real effect on mood levels. As previously mentioned, TKO mice may undergo spontaneous epileptic seizures (Boido et al., 2010; Cambiaghi et al., 2013; Farisello et al., 2013; Gitler et al., 2004), especially during cage changing procedures (Ketzef et al., 2011). Although during the experimental procedures we did not observe spontaneous/induced epileptic episodes, we cannot rule out the possible effect of epileptic seizures occurring before the experiments upon the observed behavioral outcomes.
Growth and excitability at synapsin II deficient hippocampal neurons
2019, Molecular and Cellular NeuroscienceSynapsin-antibodies in psychiatric and neurological disorders: Prevalence and clinical findings
2017, Brain, Behavior, and ImmunityClassical neurotransmitters and neuropeptides involved in generalized epilepsy in a multi-neurotransmitter system: How to improve the antiepileptic effect?
2017, Epilepsy and BehaviorCitation Excerpt :Levetiracetam is used in children for the treatment of refractory generalized epilepsy. It increases the inhibitory/excitatory effect in cerebral cortex (I–IV layers) neurons, for example, it increases the presynaptic inhibitory effect of GABAergic neurons and reduces the excitotoxic effect of glutaminergic neurons by blocking NMDA receptors [38]. Rufinamide is a new AED used for adjunctive pharmacotherapy of seizures in Lennox–Gastaut syndrome in children of 4 years of age or older.
- 1
These authors contributed equally.