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,

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

Molecular And Cellular NeurobiologyPoster Number (127) Session IIDIFFERENTIAL CONSEQUENCE OF GAIN-OF-FUNCTIONFHM1 MUTATION ON NEURONS IN KNOCK-IN MICEDEPENDING ON THE DURATION OF THE ACTION POTENTIAL.González Inchauspe Carlota1, Urbano Francisco J.1, Di GuilmiMariano N.1, Ferrari Michel D. 2, van den Maagdenber Arn M.J.M. 2,Uchitel Osvaldo D.11Instituto de Fisiología, Biología molecular y Neurociencias. CONICET.Departamento de Fisiología, Biología Molecular y Celular, Facultad de CienciasExactas y Naturales, UBA., 2Department of Neurology, Leiden University MedicalCentre, The Netherlands. carlota@fbmc.fcen.uba.arFamilial hemiplegic migraine type-1 (FHM1) is caused by missensemutations in the CACNA1A gene that encodes the α1A pore-forming subunitof Cav2.1 P/Q-type Ca2+ channels. We have used knock-in (KI) transgenicmice harbouring the pathogenic FHM1 mutation R192Q to study thephysiology of neurotransmission at the calyx of Held glutamatergic synapse.Using whole cell patch clamp in brainstem slices we confirmed that KI P/QtypeCa2+ channels activate at more hyperpolarizing potentials and havesmaller activation time constants. In spite of that, presynaptic calcium currents(IpCa) evoked by presynaptic action potentials (APs) in these neurons aresimilar in their amplitudes and kinetic parameters. Since migraine is closelyrelated to altered properties of cortical circuits, we extended our studies tocortical layer 2/3 pyramidal neurons. These have longer durations and smalleramplitude APs than those at the calyx of Held, thus allowing us to comparedifferent APs waveforms to elicit Ca2+ currents. We observed the same shift inthe voltage activation of calcium currents (ICa) but in contrast to the calyx ofHeld IpCa, P/Q-type ICa evoked by APs of cortical pyramidal neurons showedincreased amplitudes in KI compared to WT mice. Instead, when P/Q-typeICa were evoked in pyramidal neurons by calyx of Held APs waveforms, wefound no amplitude differences between WT and KI mice. Our results suggestthat the longer depolarizing time course of APs is an important factor for theexpression of a synaptic gain of function in KI mice. In addition, they show thatthe consequences of FHM1 mutations may vary in different excitatory neurons(glutmatergic neurons in the calyx of Held vs glutamatergic neurons in thecortex), which adds to the complexity of the pathophysiology of migraine.