Altered function of Cav2.1 calcium channels leads to changes in synaptic transmission in brain stem synapses from genetically modified CACNA1A mice.

CARLOTA GONZÁLEZ INCHAUSPE; BÁRBARA GIUGOVAZ TROPPER; ARN M.J.M VAN DEN MAAGDENBERG; RUNE R. FRANTS; MICHEL D. FERRARI; OSVALDO D. UCHITEL

Los Cocos, Córdoba, Argentina.

Congreso; XXII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2007

Sociedad Argentina de Investigación en Neurociencias

Genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage dependent Ca2+ channel a1A subunit with hereditary neurological disorders. The generation of a knockin mice with the R192Q familial hemiplegic migraine (FHM1) mutation allows a critical examination of features of neurotransmission dependent on Ca2+ influx. We used auditory brainstem slices containing the Medial Nucleus of the Trapezoid Body (MNTB), whose principal neurons receive a giant synapse (calyx of Held). Whole cell patch clamp technique was used to measure presynaptic Ca2+ currents (IpCa) at the calyx of Held nerve terminal and neurotransmitter induced excitatory postsynaptic currents (EPSCs) at the MNTB and LSO neurons. The current–voltage (I–V) relationship of IpCa revealed that Cav2.1 Ca2+ channels activate at more negative potentials in R192Q KI and at more positive potentials in the KO mice. Nevertheless, IpCa induced by action potential show only a small increase in KI presynaptic terminals, which is not significant different from WT ones.        No differences were observed in the amplitude of EPSC at KI synapses. However some short term plasticity phenomena are altered. Repetitive firings cause short term depression (STD), due to rapid depletion of synaptic vesicles, which recovers after many seconds of rest during which replenishment of the readily releasable pool of synaptic vesicles occurs. Recovery from STD induced by 10 and 100 Hz stimulation of the MNTB and 10 and 20 Hz stimulation of the LSO afferent axons is significantly faster in KI than in the WT animals. To asses the role of residual calcium on the kinetics of recovery, we also studied the recovery process under the effect of a slow Ca2+ buffer (EGTA-AM, 0.2 mM) into presynaptic calyces. These results are in line with the hypothesis of a gain of function of the KI mutation. It has been proposed that both release and replenishment of synaptic vesicles are highly dependent on the level of Ca2+ influx. Such influx may provide an important gain control mechanism to adjust synaptic strength. Therefore, alterations in the degree or kinetics of these phenomena could result in important changes in network activity leading to ataxia epilepsy and migraine.