Vecchia Dania, Tottene Angelita, van den Maagdenberg Arn M J M, Pietrobon Daniela
Department of Biomedical Sciences, University of Padova and CNR Institute of Neuroscience, 35121 Padova, Italy.
Department of Human Genetics and Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
Neurobiol Dis. 2014 Sep;69(100):225-34. doi: 10.1016/j.nbd.2014.05.035. Epub 2014 Jun 5.
Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca(2+)] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory-inhibitory balance in FHM1.
家族性偏瘫型偏头痛1型（FHM1）是偏头痛伴先兆的单基因亚型，由CaV2.1（P/Q型）钙通道的功能获得性突变引起。在FHM1基因敲入小鼠中，皮质锥体细胞突触处的兴奋性神经传递增强，但快速放电（FS）中间神经元与锥体细胞连接对之间的抑制性神经传递未改变，尽管其由CaV2.1通道启动。皮质FS中间神经元突触处GABA释放未改变的潜在机制仍不清楚。在此，我们表明FHM1的R192Q突变不影响来自R192Q基因敲入小鼠的微培养中皮质FS和其他类型多极中间神经元自突触处的抑制性传递，并研究其潜在机制。降低细胞外[Ca(2+)]在对照中或用四乙铵延长动作电位（AP）后均未揭示诱发传递的功能获得，表明FHM1基因敲入小鼠抑制性自突触处AP诱发的突触前钙内流未改变。突触前钙传感器的饱和或AP的短持续时间均不能解释突变小鼠中未改变的抑制性传递。对微培养中多极中间神经元P/Q型钙电流记录显示，与皮质锥体细胞中突变CaV2.1通道电流密度增强和激活门控左移相反，这些中间神经元中表达的CaV2.1通道的电流密度和门控特性几乎不受FHM1突变影响。我们的研究结果表明，在抑制性和兴奋性皮质神经元中对FHM1突变调节具有不同敏感性的特定CaV2.1通道的表达是FHM1中兴奋性突触传递功能获得但抑制性突触传递未改变以及可能随之而来皮质兴奋 - 抑制平衡失调基础。
