Synapsin II and Rab3a Cooperate in the Regulation of Epileptic and Synaptic Activity in the CA1 Region of the Hippocampus

Abstract

Some forms of idiopathic epilepsy in animals and humans are associated with deficiency of synapsin, a phosphoprotein that reversibly associates with synaptic vesicles. We have previously shown that the epileptic phenotype seen in synapsin II knock-out mice (SynII(Ϫ)) can be rescued by the genetic deletion of the Rab3a protein. Here we have examined the cellular basis for this rescue using whole-cell recordings from CA1 hippocampal pyramidal cells in brain slices. We find that SynII(Ϫ) neurons have increased spontaneous activity and a reduced threshold for the induction of epileptiform activity by 4-aminopyridine (4-AP). Using selective recordings of glutamatergic and GABAergic activity we show that in wild-type neurons low concentrations of 4-AP facilitate glutamatergic and GABAergic transmission in a balanced way, whereas in SynII(Ϫ) neurons this balance is shifted toward excitation. This imbalance reflects a deficit in inhibitory synaptic transmission that appears to be secondary to reduced Ca 2ϩ sensitivity in SynII(Ϫ) neurons. This suggestion is supported by our finding that synaptic and epileptiform activity at SynII(Ϫ) and wild-type synapses is similar when GABAergic transmission is blocked. Deletion of Rab3a results in glutamatergic synapses that have a compromised responsiveness to either low 4-AP concentrations or elevated extracellular Ca 2ϩ . These changes mitigate the overexcitable phenotype observed in SynII(Ϫ) neurons. Thus, Rab3a deletion appears to restore the excitatory/inhibitory imbalance observed in SynII(Ϫ) hippocampal slices indirectly, not by correcting the deficit in GABAergic synaptic transmission but rather by impairing excitatory glutamatergic synaptic transmission.

MicroRNA-181 promotes synaptogenesis and attenuates axonal outgrowth in cortical neurons

“…In particular, eight genes significantly altered by the miR-181c sponge play important roles in the development of neurons, namely Cast, Cav1, Cyr61, Fgfr3, Lrp4, Pdgfra, Rhoq and Syn2 [35–40]. Furthermore, an enrichment of genes involved in the activation of neurons and regulation of synaptic transmission were found, namely Apln, Ptger3, Syn2, Cast and Fbxo2 [41–43]. Together, these results suggest that miR-181c controls, through direct or indirect interactions, several gene clusters, which modulate neuronal developmental processes and synaptic function.…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…These results implicate synapsin in the regulation of network excitability and may explain the underlying cause of epileptic seizures in synapsin KO mice (Chiappalone et al, 2009). Rab3A deletion in synapsin II KO mice appears to restore the excitatory/ inhibitory balance, suggesting that the two synaptic vesicle proteins coregulate synaptic activity (Feliciano et al, 2013).…”

Subconvulsant doses of pentylenetetrazol uncover the epileptic phenotype of cultured synapsin-deficient Helix serotonergic neurons in the absence of excitatory and inhibitory inputs

“…In humans, epilepsy and other disorders have been linked to mutations in SynI (Garcia et al, 2004;Fassio et al, 2011b;Lignani et al, 2013;Giannandrea et al, 2013) and SynII genes (Cavalleri et al, 2007;Lakhan et al, 2010;Corradi et al, 2014). In addition, the seizure susceptibility of mice TKO brain slices has been reported to anticipate epileptic phenotypes (Boido et al, 2010;Feliciano et al, 2013).…”

“…It is generally accepted that Syn deficiency reduces GABAergic transmission and not affects or increases glutamatergic transmission, thus leading to a positive imbalance towards hyperexcitability (Terada et al, 1999;Gitler et al, 2004;Baldelli et al, 2007;Chiappalone et al, 2009;Ketzef et al, 2011;Farisello et al, 2012;Lignani et al, 2013;Feliciano et al, 2013;Medrihan et al, 2013;Medrihan et al, 2014 Klee, 1976 andAltrup, 2004). Finally, a key advantage of this monosynaptic cell model is that the presynaptic and postsynaptic compartments can be selectively targeted by injections and specific networks can be constructed by directly plating individual neurons on MEA electrodes.…”