Gain of function in FHM-1 CaV2.1 knock-in mice is related to the shape of the action potential

UCHITEL OD ; GONZALEZ-INCHAUSPE C; URBANO FJ; DI GUILMI MN; FORSYTHE ID; FERRARI MD; VAN DEN MAAGDENBERG AMJM

San Diego, USA

Congreso; 40th Annual Meeting Society for Neuroscience; 2010

Society for Neuroscience

Familial hemiplegic migraine type-1 (FHM1) is caused by missense mutations in the CACNA1A gene that encodes the á1A pore-forming subunit of CaV2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harbouring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held presynaptic terminals (CHeld PT) and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch clamp recordings in brainstem and cortical slices we confirmed that KI CaV2.1 channels activated at more hyperpolarizing potentials at both CHeld PT and PCs. We used APs recorded from the cortical layer 2/3 PCs and from the calyx of Held to compare the calcium currents (ICa) elicited by both AP waveforms. While ICa amplitudes recorded in WT or KI cortical layer 2/3 pyramidal cells showed no differences when elicited by calyx of Held AP waveforms, a significant increase in the amplitude of ICa was observed in R192Q KI compared to WT when pyramidal cell AP waveforms were used. Likewise, KI mice show an enhancement in ICa at the CHeld PT when elicited by PC APs but not when evoked by their own APs. Moreover, we have shown that ICa influx elicited using AP-like waveforms with different repolarization times became significantly larger in KI pyramidal neurons compared to WT when the waveform repolarization phase was prolonged. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice and indicate that consequences of FHM1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission. In particular, the differences in AP durations that trigger cortical excitatory and inhibitory synapses may explain the unaltered inhibitory neurotransmission observed at the fast spiking (FS) interneuron-pyramidal cell (PC) synapses and the increased probability of glutamate release observed at the PC-FS interneuron excitatory synapses in this KI model (Tottene et al, Neuron 61: 762-73, 2009). This abnormal balance of cortical excitatory-inhibitory synaptic transmission may underlie the increased susceptibility to cortical spreading depression (CSD) in KI mice, a likely mechanism of the migraine aura.