[show abstract][hide abstract] ABSTRACT: Depolarization of presynaptic terminals that arises from activation of presynaptic ionotropic receptors, or somatic depolarization, can enhance neurotransmitter release; however, the molecular mechanisms mediating this plasticity are not known. Here we investigate the mechanism of this enhancement at the calyx of Held synapse, in which presynaptic glycine receptors depolarize presynaptic terminals, elevate resting calcium levels, and potentiate release. Using knock-out mice of the calcium-sensitive PKC isoforms (PKC(Ca)), we find that enhancement of evoked but not spontaneous synaptic transmission by glycine is mediated primarily by PKC(Ca). Measurements of calcium at the calyx of Held indicate that deficits in synaptic modulation in PKC(Ca) knock-out mice occur downstream of presynaptic calcium increases. Glycine enhances synaptic transmission primarily by increasing the effective size of the pool of readily releasable vesicles. Our results reveal that PKC(Ca) can enhance evoked neurotransmitter release in response to calcium increases caused by small presynaptic depolarizations.
Journal of Neuroscience 10/2012; 32(40):13796-804. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Posttetanic potentiation (PTP) is a transient, calcium-dependent increase in the efficacy of synaptic transmission following elevated presynaptic activity. The calcium-dependent protein kinase C (PKC(Ca)) isoforms PKCα and PKCβ mediate PTP at the calyx of Held synapse, with PKCβ contributing significantly more than PKCα. It is not known whether PKC(Ca) isoforms play a conserved role in PTP at other synapses. We examined this question at the parallel fiber → Purkinje cell (PF→PC) synapse, where PKC inhibitors suppress PTP. We found that PTP is preserved when single PKC(Ca) isoforms are knocked out and in PKCα/β double knock-out (dko) mice, even though in the latter all PKC(Ca) isoforms are eliminated from granule cells. However, in contrast to wild-type and single knock-out animals, PTP in PKCα/β dko animals is not suppressed by PKC inhibitors. These results indicate that PKC(Ca) isoforms mediate PTP at the PF→PC synapse in wild-type and single knock-out animals. However, unlike the calyx of Held, at the PF→PC synapse either PKCα or PKCβ alone is sufficient to mediate PTP, and if both isoforms are eliminated a compensatory PKC-independent mechanism preserves the plasticity. These results suggest that a feedback mechanism allows granule cells to maintain the normal properties of short-term synaptic plasticity even when the mechanism that mediates PTP in wild-type mice is eliminated.
Journal of Neuroscience 09/2012; 32(38):13004-9. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: High-frequency stimulation leads to a transient increase in the amplitude of evoked synaptic transmission that is known as posttetanic potentiation (PTP). Here we examine the roles of the calcium-dependent protein kinase C isoforms PKCα and PKCβ in PTP at the calyx of Held synapse. In PKCα/β double knockouts, 80% of PTP is eliminated, whereas basal synaptic properties are unaffected. PKCα and PKCβ produce PTP by increasing the size of the readily releasable pool of vesicles evoked by high-frequency stimulation and by increasing the fraction of this pool released by the first stimulus. PKCα and PKCβ do not facilitate presynaptic calcium currents. The small PTP remaining in double knockouts is mediated partly by an increase in miniature excitatory postsynaptic current amplitude and partly by a mechanism involving myosin light chain kinase. These experiments establish that PKCα and PKCβ are crucial for PTP and suggest that long-lasting presynaptic calcium increases produced by tetanic stimulation may activate these isoforms to produce PTP.
[show abstract][hide abstract] ABSTRACT: Synapses exhibit several forms of short-term plasticity that play a multitude of computational roles. Short-term depression suppresses neurotransmitter release for hundreds of milliseconds to tens of seconds; facilitation and post-tetanic potentiation lead to synaptic enhancement lasting hundreds of milliseconds to minutes. Recent advances have provided insight into the mechanisms underlying these forms of plasticity. Vesicle depletion, as well as inactivation of both release sites and calcium channels, contribute to synaptic depression. Mechanisms of short-term enhancement include calcium channel facilitation, local depletion of calcium buffers, increases in the probability of release downstream of calcium influx, altered vesicle pool properties, and increases in quantal size. Moreover, there is a growing appreciation of the heterogeneity of vesicles and release sites and how they can contribute to use-dependent plasticity.
Current opinion in neurobiology 02/2011; 21(2):269-74. · 7.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Throughout the brain, multiple interneuron types influence distinct aspects of synaptic processing. Interneuron diversity can thereby promote differential firing from neurons receiving common excitation. In contrast, Golgi cells are the sole interneurons regulating granule cell spiking evoked by mossy fibers, thereby gating inputs to the cerebellar cortex. Here, we examine how this single interneuron class modifies activity in its targets. We find that GABA(A)-mediated transmission at unitary Golgi cell --> granule cell synapses consists of varying contributions of fast synaptic currents and sustained inhibition. Fast IPSCs depress and slow IPSCs gradually build during high-frequency Golgi cell activity. Consequently, fast and slow inhibition differentially influence granule cell spike timing during persistent mossy fiber input. Furthermore, slow inhibition reduces the gain of the mossy fiber --> granule cell input-output curve, while fast inhibition increases the threshold. Thus, a lack of interneuron diversity need not prevent flexible inhibitory control of synaptic processing.
[show abstract][hide abstract] ABSTRACT: Short-term synaptic plasticity influences how presynaptic spike patterns control the firing of postsynaptic targets. Here we investigated whether specific mechanisms of short-term plasticity are regulated in a target-dependent manner by comparing synapses made by cerebellar granule cell parallel fibers onto Golgi cells (PF-->GC synapse) and Purkinje cells (PF-->PC synapse). Both synapses exhibited similar facilitation, suggesting that any differential short-term plasticity does not reflect differences in the initial release probability. PF-->PC synapses were highly sensitive to stimulus bursts, which could result in either depression of subsequent responses, mediated by endocannabinoid-dependent retrograde signaling, or enhancement of responses through posttetanic potentiation (PTP). In contrast, stimulus bursts had remarkably little effect on the strength of PF-->GC synapses. Unlike PCs, GCs were unable to regulate their PF synapses by releasing endocannabinoids. Moreover, PTP was reduced at the PF-->GC synapse compared to the PF-->PC synapse. Thus, the target-dependence of PF synapses arises from the differential expression of both retrograde signaling and PTP.