Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential

O. D. UCHITEL

Placencia, Belize

Congreso; Second International Calcium Channel Conference - Placencia, Belize; 2010

Familial hemiplegic migraine type-1 (FHM1) is caused by missense mutations in the CACNA1Agene that encodes the α1A pore-forming subunit of CaV2.1 Ca2+ channels. We have used knock-in(KI) transgenic mice harbouring the pathogenic FHM-1 mutation R192Q to study the physiologyof neurotransmission at the calyx of Held synapses and cortical layer 2/3 pyramids. Using wholecell patch clamp recordings in brainstem slices we confirmed that KI CaV2.1 Ca2+ channelsactivated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents(IpCa) evoked by presynaptic action potentials (APs) in these neurons are similar in theiramplitudes, kinetic parameters and neurotransmitter release.CaV2.1 Ca2+ channels in cortical layer 2/3 pyramids from KI mice also showed a shift in theiractivation voltage. Pyramidal cells (PCs) have APs with longer durations and smaller amplitudesthan those at the calyx of Held. In contrast to the calyx of Held synapse, Ca2+ currents (ICa) fromPCs evoked by their own APs showed an increase in amplitude in KI mice compared to WTmice. Instead, when ICa were evoked in PCs by calyx of Held AP waveforms, we observed noamplitude differences between WT and KI mice. These results suggest that the longer timecourse of pyramidal APs is an important factor for the expression of a synaptic gain of functionin the KI mice. Thus, our results show that the outcome of FHM1 mutations may vary indifferent neurons according to the shape of their action potentials.