Calcium channels and synaptic transmission in familial hemiplegic migraine type 1 animal models

One of the outstanding developments in clinical neurology has been the identification of ion channel mutations as the origin of a wide variety of inherited disorders like migraine, epilepsy, and ataxia. The study of several channelopathies has provided crucial insights into the molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological diseases. This review addresses the mutations underlying familial hemiplegic migraine (FHM) with particular interest in Cav2.1 (i.e., P/Q-type) voltageactivated Ca2+ channel FHM type-1 mutations (FHM1). Transgenic mice harboring the human pathogenic FHM1 mutation R192Q or S218L (KI) have been used as models to study neurotransmission at several central and peripheral synapses. FHM1 KI mice are a powerful tool to explore presynaptic regulation associated with expression of Cav2.1 channels. FHM1 Cav2.1 channels activate at more hyperpolarizing potentials and show an increased open probability. These biophysical alterations may lead to a gain-of-function on synaptic transmission depending upon factors such as action potential waveform and/or Cav2.1 splice variants and auxiliary subunits. Analysis of FHM knock-in mouse models has demonstrated a deficient regulation of the cortical excitation/ inhibition (E/I) balance. The resulting excessive increases in cortical excitation may be the mechanisms that underlie abnormal sensory processing together with an increase in the susceptibility to cortical spreading depression (CSD). Increasing evidence from FHM KI animal studies support the idea that CSD, the underlying mechanism of aura, can activate trigeminal nociception, and thus trigger the headache mechanisms. Fil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: González Inchauspe, Carlota María Fabiola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina