Brain-Derived Neurotrophic Factor Enhances GABA Release Probability and Nonuniform Distribution of N- and P/Q-Type Channels on Release Sites of Hippocampal Inhibitory Synapses

Istituto Nazionale di Fisica della Materia Research Unit, Nanostructured Interfaces and Surfaces Center, I-10125 Turin, Italy.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2005; 25(13):3358-68. DOI: 10.1523/JNEUROSCI.4227-04.2005
Source: PubMed

ABSTRACT Long-lasting exposures to brain-derived neurotrophic factor (BDNF) accelerate the functional maturation of GABAergic transmission in embryonic hippocampal neurons, but the molecular bases of this phenomenon are still debated. Evidence in favor of a postsynaptic site of action has been accumulated, but most of the data support a presynaptic site effect. A crucial issue is whether the enhancement of evoked IPSCs (eIPSCs) induced by BDNF is attributable to an increase in any of the elementary parameters controlling neurosecretion, namely the probability of release, the number of release sites, the readily releasable pool (RRP), and the quantal size. Here, using peak-scaled variance analysis of miniature IPSCs, multiple probability fluctuation analysis, and cumulative amplitude analysis of action potential-evoked postsynaptic currents, we show that BDNF increases release probability and vesicle replenishment with little or no effect on the quantal size, the number of release sites, the RRP, and the Ca2+ dependence of eIPSCs. BDNF treatment changes markedly the distribution of Ca2+ channels controlling neurotransmitter release. It enhances markedly the contribution of N- and P/Q-type channels, which summed to >100% ("supra-additivity"), and deletes the contribution of R-type channels. BDNF accelerates the switch of presynaptic Ca2+ channel distribution from "segregated" to "nonuniform" distribution. This maturation effect was accompanied by an uncovered increased control of N-type channels on paired-pulse depression, otherwise dominated by P/Q-type channels in untreated neurons. Nevertheless, BDNF preserved the fast recovery from depression associated with N-type channels. These novel presynaptic BDNF actions derive mostly from an enhanced overlapping and better colocalization of N- and P/Q-type channels to vesicle release sites.

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Available from: Emilio Carbone, Sep 27, 2015
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    • "Interestingly, early work on these effects performed in the rat hippocampus yielded a number of conflicting results, unveiling a more complex picture than expected. Indeed, in juvenile rodents BDNF was found to favor a substantial depression of GABAergic transmission via either pre- or postsynaptic mechanisms [42, 43]; conversely, studies in immature neurons showed an overall potentiating effect [44, 45]. To explain such a discrepancy, it was hypothesized that the effect of BDNF onto GABAergic transmission in hippocampal neurons might be developmentally regulated in parallel with the switch in GABAergic transmission from excitatory to inhibitory [46]. "
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    • "It has mainly been targeted on non-L-type channels (Jeong and Wurster 1997; Delmas et al. 1998; Stewart et al. 1999; Liu et al. 2002) through activation of PI3K/Ca 2+ -independent and PLC/Ca 2+ -dependent PKC (Salgado et al. 2007). N-and P/Q-types are the main calcium channels involved in the GABA release of hippocampal neurons (Baldelli et al. 2005). In our study, we have showed that somatic N-and P/Q-types are more sensitive than L-and R-types to muscarinic modulation. "
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