Short‐term synaptic plasticity, simulation of nerve terminal dynamics, and the effects of protein kinase C activation in rat hippocampus

Abstract

Phorbol esters are hypothesised to produce a protein kinase C (PKC)-dependent increase in the probability of transmitter release via two mechanisms: facilitation of vesicle fusion or increases in synaptic vesicle number and replenishment. We used a combination of electrophysiology and computer simulation to distinguish these possibilities. We constructed a stochastic model of the presynaptic contacts between a pair of hippocampal pyramidal cells that used biologically realistic processes and was constrained by electrophysiological data. The model reproduced faithfully several forms of short-term synaptic plasticity, including short-term synaptic depression (STD), and allowed us to manipulate several experimentally inaccessible processes. Simulation of an increase in the size of the readily releasable vesicle pool and the time of vesicle replenishment decreased STD, whereas simulation of a facilitation of vesicle fusion downstream of Ca 2+ influx enhanced STD. Because activation of protein kinase C with phorbol ester enhanced STD of EPSCs in rat hippocampal slice cultures, we conclude that an increase in the sensitivity of the release process for Ca 2+ underlies the potentiation of neurotransmitter release by PKC.

Activity-Dependent Release of Adenosine Contributes to Short-Term Depression at CA3-CA1 Synapses in Rat Hippocampus

“…The EPSC depression that remains in the presence of DPCPX presumably results from the depletion of readily releasable synaptic vesicles (e.g., Brager et al 2002;Dobrunz and Stevens 1997;Wu and Borst 1999). At other CNS synapses (e.g., Motley and Collins 1983;von Gersdorff et al 1997), presynaptic inhibitory receptors also participate in homosynaptic STD, but their contribution is considerably smaller than the effect of adenosine reported here.…”

“…1A). STD was accompanied by a significant increase in paired-pulse ratio (PPR) and a significant decrease in the inverse square at the coefficient of variation (CV Ϫ2 ) (Brager et al 2002), indicating that a decrease in the probability of neurotransmitter release underlies STD.…”

Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation

“…Consistent with the proposed role of PKC in the regulation of synaptic efficacy, exogenous activation of PKC with phorbol esters induces the movement of neurotransmitter vesicles from reserve pools to the readily releasable pool at active release sites (Stevens and Sullivan, 1998;Brager et al, 2002;Shoji-Kasai et al, 2002;Kumakura et al, 2004), which is positively correlated with synaptic release probability (Schikorski and Stevens, 1997). The maintenance of synaptic vesicles in reserve pools, and their movement to the readily releasable pool, is also regulated by the filamentous (F) actin cytoskeleton (Gotow et al, 1991;Doussau and Augustine, 2000;Morales et al, 2000;Trifaro et al, 2002), and accumulating evidence suggests that the maintenance phase of LTP requires synaptic F-actin cytoskeletal assembly-disassembly dynamics (Kim and Lisman, 1999;Krucker et al, 2000;Fukazawa et al, 2003;Lang et al, 2004;Matsuzaki et al, 2004).…”

“…Furthermore, the failure to observe PPF deficits in heterozygous Marcks mutant mice suggest that intracellular calcium homeostasis is not impaired by 50% reductions in MARCKS expression, even though MARCKS binds calcium-calmodulin at elevated calcium levels in a PKC phosphorylation-reversible manner (Porumb et al, 1997). PTP refers to the transient increase in glutamate release immediately following HFS, and is associated with the depletion of the readily releasable vesicle pool in a PKC-regulated manner (Brager et al, 2002(Brager et al, , 2003. In the present study, heterozygous Marcks mutant mice exhibited a nonsignificant reduction (~30%) in PTP in the mossy fiber-CA3 pathway, but not in the Schaffer collateral-CA1 pathway, relative to wild-type mice.…”

“…Therefore, a 50% reduction in MARCKS in mossy fiber axon terminals may compromise the regulation of F-actin cytoskeletal rigidity, resulting in less restriction in the movement of synaptic vesicles from reserve pools to active release sites. Since PTP is associated with the initial depletion of the readily-release vesicle pool (Brager et al, 2002) and is followed by a redistribution of synaptic vesicles from reserve pools to the readily-release pool (Applegate et al, 1987;Brager et al, 2002), a failure to maintain vesicles in reserve/surplus pools would be predicted to impair long-term, but not short-term, elevations in neurotransmitter release probability (Markram and Tsodyks, 1996;Stevens and Sullivan, 1998;Yawo, 1999;Brager et al, 2002). If this model is correct, future ultrastuctural analysis of mossy fiber terminals should reveal a paucity of vesicles in reserve pools in heterozygous Marcks mutant mice.…”