Kinetics alterations and reduced calcium currents at the calyx of Held in a S218L Cav 2.1 knockin migraine mouse model .

DI GUILMI MARIANO N.; GONZALEZ INCHAUSPE C; FORSYTH IAN ; VAN DEN MAAGDENBERG, A.; BORST GERARD J.; UCHITEL OSVALDO D.

Florencia

Congreso; 8Th IBRO World congress of Neuroscience; 2011

IBRO

Genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage dependent Ca2+ channel á1A subunit with hereditary neurological disorders. The generation of á1A knock-in (KI) mice with the S218L familial hemiplegic migraine (FHM1) mutation (Tottone et. al. 2005) allows a critical examination of features of neurotransmission dependent on Ca2+ influx. Familial hemiplegic migraine type-1 (FHM1) is caused by missense mutations in the CaV2.1 Ca2+ channel. We used KI transgenic mice with the pathogenic FHM-1 mutation S218L to study Ca2+ current alterations at the calyx of Held. Using whole-cell patch-clamp recordings, a shift of the peak of the I-V curve to more negative potentials was observed (WT: -10 mV, n=10; KI: -20 mV, n=5). The steady-state activation curves were significantly different between WT and KI mice, activating at more negative potentials in the transgenic model (-23.0 ± 1.7 mV, n=7 for WT and -36.7±6.5 mV, n=5 for KI). The activation of IpCa was faster in the KI than WT mouse in the range between -30 and + 20 mV. On the other hand, presynaptic calcium currents (IpCa) evoked by action potential (AP) waveforms had less amplitude in KI than WT (1.6±0.2 nA, n=9 for WT and 0.9±02 nA, n=5 for KI). Additionally, Ca2+ current facilitation after 100 Hz train of APs was significant reduced in KI compared to WT mice (20±2.5%, n=8 for WT and KI 7±2%, n=5 for KI). It is expected that these alterations in channel properties due to the FHM1 mutation will produce profound changes in synaptic transmission at the calyx of Held synapse.