Calcium current alterations at the calyx of held in S218L KI mice mutant

DI GUILMI MARIANO N.; GONZÁLEZ INCHAUSPE C.; FORSYTHE IAN D; VAN DEN MAAGDENBER ARN; FERRARI MICHEL D; BORST J; GERARD G.; UCHITEL O. D.

Huerta Grande, Córdoba

Congreso; II Reunión Conjunta de la Sociedad Argentina de Neurociencias; 2010

Familial hemiplegic migraine type-1 (FHM1) is caused by missense mutations in the CaV2.1 Ca2+ channel. We used knock-in (KI) transgenic mice with the pathoge­nic FHM-1 mutation S218L to study Ca2+ current alterations at the calyx of Held. Due to the fact that the human disease is expressed in a heterozygote (Het) mode, we decided to focalize our studies in this genotype. Using whole-cell patch-clamp recordings, a shift was found in the I-V curve at more negative potentials (WT: -10 mV; Het: -15 mV; KI: -20 mV). The steady-state activation curves were significantly different between WT and Het mice. Presynaptic calcium currents evoked at the calyx of Held of WT or Het mice by their own action potentials (APs) were simi­lar in amplitude. However Het mice showed an increase in IpCa amplitudes when evoked by the longer AP waveforms characteristic of the pyramidal cells. Aditio­nally, Ca2+ current facilitation after 100 Hz train of APs is reduced in Het com­pared to WT mice. Our results suggest that: 1) longer time courses of pyramidal cell APs are a key factor for the expression of a synaptic gain of function in the mutated mice as it was demonstrated in other transgenic mice model (R192Q); 2) activation/inactivation properties of CaV2.1 Ca2+ channels are modified by the mutation.