At Immature Mossy-Fiber–CA3 Synapses, Correlated Presynaptic and Postsynaptic Activity Persistently Enhances GABA Release and Network Excitability via BDNF and cAMP-Dependent PKA

Abstract

In the adult rat hippocampus, the axons of granule cells in the dentate gyrus, the mossy fibers (MF), form excitatory glutamatergic synapses with CA3 principal cells. In neonates, MF release into their targets mainly GABA, which at this developmental stage is depolarizing. Here we tested the hypothesis that, at immature MF-CA3 synapses, correlated presynaptic [single fiber-evoked GABA A -mediated postsynaptic potentials (GPSPs)] and postsynaptic activity (back propagating action potentials) may exert a critical control on synaptic efficacy. This form of plasticity, called spike-timing-dependent plasticity (STDP), is a Hebbian type form of learning extensively studied at the level of glutamatergic synapses. Depending on the relative timing, pairing postsynaptic spiking and single MF-GPSPs induced bidirectional changes in synaptic efficacy. In case of positive pairing, spike-timing-dependent-long-term potentiation (STD-LTP) was associated with a persistent increase in GPSP slope and in the probability of cell firing. The transduction pathway involved a rise of calcium in the postsynaptic cell and the combined activity of cAMP-dependent PKA (protein kinase A) and brain-derived neurotrophic factor (BDNF). Retrograde signaling via BDNF and presynaptic TrkB receptors led to a persistent increase in GABA release. In "presynaptically" silent neurons, the enhanced probability of GABA release induced by the pairing protocol, unsilenced these synapses. Shifting E GABA from the depolarizing to the hyperpolarizing direction with bumetanide failed to modify synaptic strength. Thus, STD-LTP of GPSPs provides a reliable way to convey information from granule cells to the CA3 associative network at a time when glutamatergic synapses are still poorly developed.

In the Developing Rat Hippocampus, Endogenous Activation of Presynaptic Kainate Receptors Reduces GABA Release from Mossy Fiber Terminals

“…In agreement with previous studies (Gutiérrez et al, 2003;Kasyanov et al, 2004;Safiulina et al, 2006;Safiulina and Cherubini, 2009;Sivakumaran et al, 2009), during the first week of postnatal life, minimal stimulation of granule cells in the dentate gyrus elicited lowprobability GPSCs, which were completely blocked by bicuculline (10 M) or picrotoxin (100 M). Depolarizing the cell to positive potentials (ϩ40 mV) produced bicuculline-sensitive outward currents with latency, onset, and deactivation kinetics similar to those obtained at Ϫ70 mV, further indicating that they were mediated by GABA A receptors (data not shown) (Safiulina et al, 2006).…”

“…In six cases, stimulation of granule cells in the dentate gyrus failed to produce any synaptic response to the first stimulus (over at least 30 consecutive trials). However, occasional responses to the second stimulus suggested that these synapses were "presynaptically" silent (Gasparini et al, 2000;Kasyanov et al, 2004;Safiulina and Cherubini, 2009;Sivakumaran et al, 2009). Application of UBP 302 to "presynaptically" silent cells induced the appearance of synaptic responses to the first stimulus (supplemental Fig.…”

“…Signaling via presynaptic GluK1 containing KARs has been shown to be critical for regulating the number of functional glutamatergic synapses (Vesikansa et al, 2007) and the balance between GABAergic and glutamatergic transmission, which control correlated network activity . Interestingly, during the first week of postnatal life, the main neurotransmitter released from MF terminals is GABA (Safiulina et al, 2006), which exerts a depolarizing and excitatory action on targeted cells (Sivakumaran et al, 2009). MF-evoked glutamatergic currents comprising a kainate component start appearing after postnatal day 6 (P6) (Marchal and Mulle, 2004).…”

Spike-Timing-Dependent Plasticity Induces Presynaptic Changes at Immature Hippocampal Mossy Fiber Synapses

“…In a recent study published in The Journal of Neuroscience, Sivakumaran et al (2009) elegantly explored the presence of STDP at hippocampal Mf-CA3 pyramidal cell synapses. They examined this issue during an early postnatal period (postnatal day 2-5) when these synapses are thought to operate mainly through depolarizing GABA A synaptic currents (Safiulina et al, 2006).…”

“…Mechanistically, Sivakumaran et al (2009) found that STDP-LTP of GPSCs depended on postsynaptic calcium rise, postsynaptic protein kinase A (PKA) activity, and TrkB [brain-derived neurotrophic factor (BDNF) receptor] receptor activation. The authors hypothesize that the pairing protocol induced an activitydependent release of BDNF from CA3 pyramidal cells, which in turn acted presynaptically at mossy fiber terminals to increase probability of release.…”