DIFFERENTIAL CONSEQUENCE OF GAIN-OF-FUNCTION FHM1 MUTATION ON NEURONS IN KNOCK-IN MICE DEPENDING ON THE DURATION OF THE ACTION POTENTIAL.

GONZÁLEZ INCHAUSPE CARLOTA; URBANO FRANCISCO J.; DI GUILMI MARIANO N; FERRARI MICHEL D.; VAN DEN MAAGDENBER ARN M.J.M.; UCHITEL OSVALDO D.

Huerta Grande, Cordoba

Congreso; First Joint Meeting of the Argentine Society for Neurosciences (SAN) and the Argentine Workshop in Neurosciences (TAN); 2009

SAN-Taller de Neurociencias

Familial hemiplegic migraine type-1 (FHM1) is caused by missense mutations in the CACNA1A gene that encodes the á1A pore-forming subunit of Cav2.1 P/Q-type Ca2+ channels. We have used knock-in (KI) transgenic mice harbouring the pathogenic FHM1 mutation R192Q to study the physiology of neurotransmission at the calyx of Held glutamatergic synapse. Using whole cell patch clamp in brainstem slices we confirmed that KI P/Q-type Ca2+ channels activate at more hyperpolarizing potentials and have smaller activation time constants. In spite of that, presynaptic calcium currents (IpCa) evoked by presynaptic action potentials (APs) in these neurons are similar in their amplitudes and kinetic parameters. Since migraine is closely related to altered properties of cortical circuits, we extended our studies to cortical layer 2/3 pyramidal neurons. These have longer durations and smaller amplitude APs than those at the calyx of Held, thus allowing us to compare different APs waveforms to elicit Ca2+ currents. We observed the same shift in the voltage activation of calcium currents (ICa) but in contrast to the calyx of Held IpCa, P/Q-type ICa evoked by APs of cortical pyramidal neurons showed increased amplitudes in KI compared to WT mice. Instead, when P/Q-type ICa were evoked in pyramidal neurons by calyx of Held APs waveforms, we found no amplitude differences between WT and KI mice. Our results suggest that the longer depolarizing time course of APs is an important factor for the expression of a synaptic gain of function in KI mice. In addition, they show that the consequences of FHM1 mutations may vary in different excitatory neurons (glutmatergic neurons in the calyx of Held vs glutamatergic neurons in the cortex), which adds to the complexity of the pathophysiology of migraine.