CONICET | Buscador de Institutos y Recursos Humanos

Cav2.1 (P/Q-type) Ca2+ channels are located throughout the mammalian nervous system at presynaptic terminals, where they play a prominent role in controlling neurotransmitter release. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the pore-forming a1 subunit of voltage-gated neuronal Cav2.1 Ca2+ channels. We used auditory brainstem slices from KI transgenic mice with the pathogenic FHM-1 human mutation R192Q in the CACNA1A gene to investigate, with the whole cell patch clamp technique, presynaptic Ca2+ currents (Ipca) from the calyx of Held nerve terminal and excitatory postsynaptic currents (EPSCs) at the soma of the neurons in the medial nucleus of the trapezoid body (MNTB). In both WT and KI synapses, Ca2+ currents were predominantly mediated by P/Q type Ca2+ channels, with w-agatoxin IVA blocking 90% of the Ca2+ currents. No differences were found in the density and facilitation of Ipca, neither in facilitation of transmitter release (EPSCs). However, the currentvoltage (IV) relationship revealed that Cav2.1 Ca2+ channels activate at more negative potentials in KIN than in WT mice. Measuring the steady state activation parameter together with the activation and deactivation time constants with different voltages steps protocols, a Hodgkin-Huxley model was used to reproduce the time course and amplitude of Ipca during an action potential. Activity dependent synaptic plasticity phenomena, such us short term depression of EPSCs in response to high frequency stimulation was also studied. It has been found that the rate of recovery from synaptic depression was faster in KI mice than in WT. These studies in the CNS synapses support the idea that a gain-of-function of Cav2.1 channels might underlie alterations in cortical excitability responsible for FHM.