Selective muscarinic regulation of functional glutamatergic Schaffer collateral synapses in rat CA1 pyramidal neurons

Abstract

Analysis of the cholinergic regulation of glutamatergic neurotransmission is an essential step in understanding the hippocampus because it can influence forms of synaptic plasticity that are thought to underlie learning and memory. We studied in vitro the cholinergic regulation of excitatory postsynaptic currents (EPSCs) evoked in rat CA1 pyramidal neurons by Schaffer collateral (SC) stimulation. Using ‘minimal’ stimulation, which activates one or very few synapses, the cholinergic agonist carbamylcholine (CCh) increased the failure rate of functional more (36 %) than of silent synapses (7 %), without changes in the EPSC amplitude. These effects of CCh were insensitive to manipulations that increased the probability of release, such as paired pulse facilitation, increases in temperature and increases in the extracellular Ca2+ : Mg2+ ratio. Using ‘conventional’ stimulation, which activates a large number of synapses, CCh inhibited more the pharmacologically isolated non‐NMDA (86 %) than the NMDA (47 %) EPSC. The changes in failure rate, EPSC variance and the increased paired pulse facilitation that paralleled the inhibition imply that CCh decreased release probability. Muscarine had similar effects. The inhibition by both CCh and by muscarine was prevented by atropine. We conclude that CCh reduces the non‐NMDA component of SC EPSCs by selectively inhibiting transmitter release at functional synapses via activation of muscarinic receptors. The results suggest that SCs have two types of terminals, one in functional synapses, selectively sensitive to regulation through activation of muscarinic receptors, and the other in silent synapses less sensitive to that regulation. The specific inhibition of functional synapses would favour activity‐dependent plastic phenomena through NMDA receptors at silent synapses without the activation of non‐NMDA receptors and functional synapses.

Enhanced cholinergic suppression of previously strengthened synapses enables the formation of self-organized representations in olfactory cortex

“…In this manner, the newly potentiated synaptic strength could be more sensitive to cholinergic modulation of ''functional'' synapses, whereas the baseline activity could involve a less sensitive set of synapses. The evidence for selective effects of carbachol at one type of glutamatergic synapse but not another in that previous study (de Sevilla et al, 2002) supports the separate modulatory influence reported here.…”

“…Note that the use of minimal stimulation (de Sevilla et al, 2002) prevents NMDA currents from appearing in neurons at resting potential, whereas the stronger stimulation used in our study probably caused more extensive activation of NMDA currents due to strong depolarization caused by extensive AMPA currents on the dendrites. Thus, synapses which are ''silent'' with minimal stimulation (de Sevilla et al, 2002) can probably contribute significantly to the field potentials evoked with stronger stimulation in our study. Those recent results provide a potential mechanism for the effects we have observed, because long-term potentiation has been shown to involve increased insertion of AMPA receptors into the postsynaptic membrane.…”

Distinct Transmitter Release Properties Determine Differences in Short-Term Plasticity at Functional and Silent Synapses

“…Cholinergic agonists inhibit transmitter release at the presynaptic terminals of functional synapses, but they do not affect silent synapses (de Sevilla et al 2002), suggesting that functional and silent synapses are both post-and presynaptically different. However, the molecular mechanisms underlying the presynaptic functional differences between both glutamatergic types of synapse remain elusive.…”

“…The effects of carbamilcholine chloride (CCh), which decreases the probability of release and manipulations that increase the probability of release, did not modify the EPSC amplitude in silent and in those functional synapses (de Sevilla et al 2002). However, in that same publication we noted that a group (Ϸ50%) of functional SC synapses showed both a decrease of the percentage of failures and an increase of the amplitude of the second EPSC (R2) during paired-pulse stimulation, and that the presynaptic inhibition by CCh could increase the percentage of failures and decrease the EPSC amplitude (de Sevilla et al 2002).…”

“…In our previous publication, we concentrated our analysis on silent synapses and on a group of functional synapses that showed changes in the percentage of failures but no modifications of the excitatory postsynaptic current (EPSC) amplitude (i.e., averages excluding failures; see following text) during PPF, a presynaptic form of short-term plasticity (de Sevilla et al 2002;Kamiya and Zucker 1994;Katz and Miledi 1968;Martín and Buño 2003;Zucker and Regehr 2002). The effects of carbamilcholine chloride (CCh), which decreases the probability of release and manipulations that increase the probability of release, did not modify the EPSC amplitude in silent and in those functional synapses (de Sevilla et al 2002).…”