Synapsin II and Rab3a cooperate in the regulation of epileptic and synaptic activity in the CA1 region of the hippocampus.
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(-)) 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(-) 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(-) neurons this balance is shifted toward excitation. This imbalance reflects a deficit in inhibitory synaptic transmission that appears to be secondary to reduced Ca(2+) sensitivity in SynII(-) neurons. This suggestion is supported by our finding that synaptic and epileptiform activity at SynII(-) 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(2+). These changes mitigate the overexcitable phenotype observed in SynII(-) neurons. Thus, Rab3a deletion appears to restore the excitatory/inhibitory imbalance observed in SynII(-) hippocampal slices indirectly, not by correcting the deficit in GABAergic synaptic transmission but rather by impairing excitatory glutamatergic synaptic transmission.
Neuroscience Department, Universidad Central del Caribe, Bayamon, Puerto Rico 00956, and Department of Pharmacology Wayne State University School of Medicine, Detroit, Michigan 48001.
Pedro
P
Feliciano
Rodrigo
R
Andrade
Maria
M
Bykhovskaia
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D016704:Synapsins / Q000172:deficiency* / Q000235:genetics; D020826:rab3A GTP-Binding Protein / Q000172:deficiency* / Q000235:genetics
D016704:Synapsins; D020826:rab3A GTP-Binding Protein