2381/29114 Carlota Gonzalez Inchauspe Carlota Gonzalez Inchauspe Francisco J. Urbano Francisco J. Urbano Mariano N. Di Guilmi Mariano N. Di Guilmi Michel D. Ferrari Michel D. Ferrari Arn M. J. M. van den Maagdenberg Arn M. J. M. van den Maagdenberg Ian D. Forsythe Ian D. Forsythe Osvaldo D. Uchitel Osvaldo D. Uchitel Presynaptic Ca[subscript v]2.1 calcium channels carrying familial hemiplegic migraine mutation R192Q allow faster recovery from synaptic depression in mouse calyx of Held University of Leicester 2014 Science & Technology Life Sciences & Biomedicine Neurosciences Physiology Neurosciences & Neurology NEUROSCIENCES PHYSIOLOGY R192Q knock-in mice familial hemiplegic migraine Ca(v)2.1 channels excitatory postsynaptic currents short-term synaptic plasticity CORTICAL SPREADING DEPRESSION TRANSMITTER RELEASE RATES SHORT-TERM PLASTICITY FUNCTIONAL CONSEQUENCES PYRAMIDAL NEURONS K+ CHANNELS TRANSMISSION VESICLES MICE INACTIVATION 2014-09-25 08:53:47 Journal contribution https://figshare.le.ac.uk/articles/journal_contribution/Presynaptic_Ca_subscript_v_2_1_calcium_channels_carrying_familial_hemiplegic_migraine_mutation_R192Q_allow_faster_recovery_from_synaptic_depression_in_mouse_calyx_of_Held/10144103 Ca[subscript V]2.1 Ca[superscript 2+] channels have a dominant and specific role in initiating fast synaptic transmission at central excitatory synapses, through a close association between release sites and calcium sensors. Familial hemiplegic migraine type 1 (FHM-1) is an autosomal-dominant subtype of migraine with aura, caused by missense mutations in the CACNA1A gene that encodes the α[subscript 1A] pore-forming subunit of Ca[subscript V]2.1 channel. We used knock-in (KI) transgenic mice harboring the FHM-1 mutation R192Q to study the consequences of this mutation in neurotransmission at the giant synapse of the auditory system formed by the presynaptic calyx of Held terminal and the postsynaptic neurons of the medial nucleus of the trapezoid body (MNTB). Although synaptic transmission seems unaffected by low-frequency stimulation in physiological Ca[superscript 2+] concentration, we observed that with low Ca[superscript 2+] concentrations (<1 mM) excitatory postsynaptic currents (EPSCs) showed increased amplitudes in R192Q KI mice compared with wild type (WT), meaning significant differences in the nonlinear calcium dependence of nerve-evoked transmitter release. In addition, when EPSCs were evoked by broadened presynaptic action potentials (achieved by inhibition of K[superscript +] channels) via Ca[subscript v]2.1-triggered exocytosis, R192Q KI mice exhibited further enhancement of EPSC amplitude and charge compared with WT mice. Repetitive stimulation of afferent axons to the MNTB at different frequencies caused short-term depression of EPSCs that recovered significantly faster in R192Q KI mice than in WT mice. Faster recovery in R192Q KI mice was prevented by the calcium chelator EGTA-AM, pointing to enlarged residual calcium as a key factor in accelerating the replenishment of synaptic vesicles.