IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential
Autor/es:
CARLOTA GONZALEZ INCHAUSPE; FRANCISCO J. URBANO; M. N. DI GUILMI; OSVALDO D. UCHITEL
Lugar:
San Diego, California
Reunión:
Congreso; 40º Annual Meeting of The Society for Neuroscience; 2010
Institución organizadora:
The Society for Neuroscience
Resumen:
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 ICaCACNA1A 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 ICaá1A 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 ICaV2.1 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 ICaCa) 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.Ca 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.Ca 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.Ca 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.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.