Gain of function of familial hemiplegic migraine type 1 R192Q calcium channel mutation on Calyx of Held presynaptic P/Q-type calcium currents

GONZÁLEZ INCHAUSPE C.; VAN DEN MAAGDENBERG A.; FRANTS R.R.; FERRARI M.D.; UCHITEL O.D.

New London, USA

Congreso; Gordon Research Conferences: Synaptic Transmission; 2006

Abstract 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 knockin transgenic mice with the pathogenic FHM-1 human mutation R192Q in the CACNA1A gene (Neuron 41: 701, 2004) 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 current–voltage (I–V) relationship revealed that Cav2.1 Ca2+ channels activate at more negative potentials in KIN than in WT mice. Short term depression of EPSCs in response to high frequency stimulation was not altered. However, the rate of recovery from synaptic depression has been found to be 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.