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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
journal contributionposted on 25.09.2014, 08:53 by Carlota Gonzalez Inchauspe, Francisco J. Urbano, Mariano N. Di Guilmi, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg, Ian D. Forsythe, Osvaldo D. Uchitel
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.
CitationJournal of Neurophysiology, 2012, 108 (11), pp. 2967-2976
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Cell Physiology and Pharmacology
Published inJournal of Neurophysiology
PublisherAmerican Physiological Society
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Science & TechnologyLife Sciences & BiomedicineNeurosciencesPhysiologyNeurosciences & NeurologyNEUROSCIENCESPHYSIOLOGYR192Q knock-in micefamilial hemiplegic migraineCa(v)2.1 channelsexcitatory postsynaptic currentsshort-term synaptic plasticityCORTICAL SPREADING DEPRESSIONTRANSMITTER RELEASE RATESSHORT-TERM PLASTICITYFUNCTIONAL CONSEQUENCESPYRAMIDAL NEURONSK+ CHANNELSTRANSMISSIONVESICLESMICEINACTIVATION