. CaV2.1 voltage activated calcium channels and synaptic transmisión in familial hemiplegic migraine pathogenesis

DI GUILMI, MN; GONZÁLEZ INCHAUSPE, C; URBANO, FJ; FORSYTHE IC; VAN DEN MAAGDENBERG A; BORST JGG, UCHITEL, OD.

New Hampshire

Workshop; Gordon Research Conference, Synaptic Transmission; 2012

Gordon Research Conference

Genes encoding the P/Q-type (CaV2.1) voltage dependent Ca2+ channel subunits have been linked to hereditary neurological disorders like familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. Although an established model explaining migraine attacks is still lacking, a favored hypothesis considers that the abnormal balance of cortical excitation?inhibition and the resulting persistent state of hyperexcitability of neurons in the cerebral cortex may be associated with the increased susceptibility for cortical spreading depression (CSD), which is believed to initiate the episodes of migraine with aura. The generation of CaV2.1 knock-in (KI) transgenic mice with mutations related to FHM1 makes it possible to study the impact of these mutations on Ca2+-dependent neurotransmission in their native neuronal environment and at their endogenous level of expression. Transgenic mice harboring the human pathogenic FHM1 mutation R192Q or S218L were used. Similar to the human FHM-1 phenotype, the S218L KI mouse has a more severe phenotype. The mutations in the CaV2.1 channels linked to FHM1 affects the biophysical properties and the density of presynaptic calcium currents (IpCa) and other properties of synaptic transmission like quantal output and short term plasticity. Calyx of Held IpCa from R192Q or S218L KI mice showed a hyperpolarizing shift in the voltage-dependence Ca2+ channel activation leading to an increased Ca2+ influx through CaV2.1 channels at more negative voltages than normal channels. The shift was more severe in the S218L KI mice. R192Q KI mice show a significant enhancement in both IpCa and excitatory postsynaptic currents (EPSCs) at the calyx of Held synapse when currents were elicited by long duration APs but not with a normal short duration AP. In contrast, S218L showed a reduction of AP evoked IpCa with significantly higher EPSC amplitudes and miniature EPSC frequencies. While in the R192Q alterations on synaptic transmission could be explained only by the shape of the AP, in S218L a presynaptic calcium influx at the resting membrane potential seems to be a key factor to induce an increase in transmitter output in spite of the reduced AP evoked IpCa. Our studies suggest that, in both models, synapses driven by short duration APs (i.e., calyx of Held and interneurons APs) are less affected by the mutation-induced hyperpolarizing shift in voltage-dependence of Ca2+ channel activation, than those driven by longer duration APs (i.e., pyramidal neurons APs). This differential expression of the gain of function may create an imbalance of cortical excitation-inhibition, resulting in an increased susceptibility for CSD in the KI mice.