Bidirectional Control of Quantal Size by Synaptic Activity in the Hippocampus

“To test this hypothesis further, we replaced extracellular calcium with strontium, a manipulation that facilitates asynchronous presynaptic vesicle release 14 (Fig.”

“…to this work. of LTP and LTD occur at the same Schaffer collateral synapses and may result from the bidirectional regulation of common molecular targets (Mulkey and Malenka, 1992; Dudek and Bear, 1993; Mulkey et al., 1993, 1994; Stevens and Wang, 1994; Heynen et al., 1996; Oliet et al., 1996).”

“Using this technique, it was possible to preferentially sample mEPSCs from the same subset of synapses that were activated to yield the evoked EPS”

“In the presence of strontium (Sr 2+ ) instead of Ca 2+ , stimulus-evoked EPSCs devolve into a series of asynchronous quantal events, each of which is identical in size to an mEPSC; this permits quantal analysis of the subset of synapses that is activated by the stimulating electrod”

“In confirmation of previous results (Oliet et al., 1996), we found a de-lease only occurs at the subset of synapses that are stimulated, it permits a detailed analysis of quantal crease in the average size of quanta during NMDARLTD (220.8% 6 7.1%, n 5 5; p , 0.05), which appearsevents originating…”

“First, LTP and LTD are accompanied by increases or decreases, respectively, in the amplitude of miniature excitatory postsynaptic currents (mEPSCs”

“approach we replaced Ca with Sr, which causes the asynchronous release of quanta from activated synapses.(33) The rationale behind the first approach was to potentiate as many synapses impinging onto the cell as possible.”

“Postsynaptic concentration of Ca 2+ ions play a role in LTP and LTD.”

“Sr21 (instead of Ca21) was included in the ACSF to produce evoked asynchronous mEPSCs (Miledi, 1966; Goda and Stevens, 1994; Oliet et al., 1996).”

“…(mEPSCs) that reflect both primary afferent and other, non-primary afferent synaptic inputs, we replaced calcium in the extracellular recording solution with strontium and evoked asynchronous quantal EPSCs (qEPSCs) from stimulated sensory afferents (Chirila et al., 2014; Oliet et al., 1996).”

“(Dodge et al., 1969; Abdul-Ghani et al., 1996; Oliet et al., 1996).”

“C, Cumulative frequency distributions of the interevent intervals of mEPSCs recorded in control cells (closed circles) and PSD-95-expressing cells (open circles). is, expressing PSD-95 enhances both the amplitude and frequency of mEPSCs, as has been reported previously for LTP (Oliet et al., 1996).”

“during the down-phase is selectively enhanced at synapses previously activated during learning (Eliot et al., 1994; Oliet et al., 1996; Bao et al., 1998; Hoffman & McNaughton, 2002), this could explain an”

“A similar conclusion was reached when Sr was used in place of Ca in the medium so that individual quanta could be resolved following synaptic stimulation [52].”

“To investigate whether physiological studies suggest that homosynaptic LTD is the functional inverse of LTP (Dudek and Bear, 1993; the HFS-induced increase in glutamate receptor protein levels is also dependent upon NMDAR activation, HFS Stevens and Wang, 1994; Heynen et al., 1996; Oliet et al., 1996).”

“…of inhibitory synapses in the dendrites of granule cells, we resorted to a technique measuring the asynchronous release of transmitter from stimulated nerve terminals when extracellular Ca 2 is replaced with equimolar Sr 2 (Oliet et al., 1996; Morishita and Alger, 1997; Rumpel and Behrends, 1999).”

“Therefore, Sr(2) is commonly used in experimental settings where quantal events associated with a specific stimulated input onto a neuron are examined (Oliet et al., 1996).”

“LTP at excitatory synapses onto these cells is expressed as an increase in the quantal size and quantal content (Malinow and Tsien, 1990; Kullmann and Nicoll, 1992; Liao et al., 1992; Malgaroli and Tsien, 1992, Oliet et al., 1996; Stricker et al., 1996).”

“In contrast, LFS-induced LTD results in a decrease in mEPSC amplitude [ 9 , 10] and a decrease in the response to application of exogenous glutamate [11].”

“, 1986; Malgaroli and Tsien, 1992; Bolshakov and Seigelbaum, 1994; Stevens and Wang, 1994), postsynaptically (Davies et al., 1989; Zalutsky and Nicoll, 1990; Manabe et al., 1992; Isaac et al., 1995; Liao et al., 1995; Oliet et al., 1996), and even on different”

“Conversely, proportional changes in AMPA receptor-mediated and NMDA receptormediated responses have been used to support a presynaptic basis for long-term plasticity.”

“For recording of miniature IPSCs (mIPSCs) in Figure 10, K-gluconate (0 mM) and KCl (150 mM) were used in internal solution, and tetrodotoxin (TTX) was added in the ACSF to block action potentials.”

“The most widespread use of strontium in the study of synaptic transmission is to desynchronize release to allow examination of the amplitude of evoked quantal events (Abdul-Ghani et al., 1996; Oliet et al., 1996; Choi and Lovinger, 1997; Morishita and Alger, 1997; Otis et al., 1997; Behrends and ten Bruggencate, 1998;…”

“NMDAR-dependent LTD is expressed via a reduction in synaptic AMPARs and is accompanied by reductions in spine size (Oliet et al., 1996; Carroll et al., 1999; Bredt and Nicoll, 2003; Zhou et al., 2004).”

“In strontium, evoked EPSCs consist of discrete, temporally dispersed mEPSC-like events (termed SrEPSCs) that represent responses to single, asynchronously released vesicles from stimulated afferents (Miledi and Slater, 1966; Dodge et al., 1969; Goda and Stevens, 1994; Oliet et al., 1996).”

“For instance, the size of “ quantal ” miniature EPSCs increases after LTP (364, 365).”

“Synchronous and asynchronous events are thought to originate from the same set of active synapses (Dodge et al. 1969; Goda & Stevens, 1994; Oliet et al. 1996; Otis et al. 1996), the asynchronous events representing unitary quantal currents (Bekkers & Clements, 1999).”

“Previous work has shown that these locally evoked events, which are due to an evoked asynchronous release of presynaptic glutamate vesicles, can be used to assess the postsynaptic strength of synapses on which the electrically stimulated axons terminate (Bain and Quastel 1992; Goda and Stevens 1998; Miledi 1966; Oliet…”

“A form of LTD that depends on NMDA receptor activation for its initiation can be induced at these same hippocampal synapses and appears to have a postsynaptic locus of expression (Stevens and Wang, 1994; Selig et al., 1995; Oliet et al., 1996, 1997).”

“Previous applications of Sr¥ to central synapses have reported that aEPSC and mEPSC amplitude distributions are identical, both for Schaffer collateral—CA1 pyramidal cell inputs (Oliet et al. 1996) and cortical inputs to the striatum (Choi & Lovinger, 1997).”

“mGluR–LTD involves mGluR1/5 activation, which generates IP3 and subsequent ER calcium release (Oliet et al., 1996).”

“Previous work by our laboratory suggests that a presynaptic ryanodine-sensitive Ca21 store is necessary for the induction of LTD by full LFS (Reyes and Stanton 1996).”

“…calyceal synapses show decay time constants which are consistently amongst the fastest recorded in central neurones (Forsythe & Barnes-Davies, 1993; Raman et al. 1994; Isaacson & Walmsley, 1996), our finding of a small absolute decrease in AMPA spontaneous EPSC ôdecay suggests that AMPA receptor…”

“Strontium is often used to isolate individual quantal currents underlying evoked release (Oliet et al., 1996; Choi and Lovinger, 1997; Morishita and Alger, 1997; Otis et al., 1997; Behrends and ten Bruggencate, 1998; Lévénès et al., 1998).”

“How can a postsynaptic response element distinguish an incoming unitary release event and trigger a distinct signaling pathway if the two forms of release originate from the same location in a terminal and activate the same population of target receptors? Under physiological conditions, unitary synaptic transmission e…”

“Delayed EPSCs are considered as quantal events in neuronal synapses because those delayed EPSCs have amplitude and kinetics similar to miniature EPSCs [113, 114].”

“This approach has been used to determine whether synaptic plasticity involves an increase in the number (frequency) and/or size (amplitude) of the quantal events 34,35 .”

“Because asynchronous release can occur at the subset of synapses that are stimulated, this allows a detailed analysis of quantal events originating from these synapses (Oliet et al., 1996, 1997; Morishita and Alger, 1997; Rumpel and Behrends, 1999).”

“Desynchronizing individual synaptic quantal events with Sr2+ (Goda & Stevens, 1994) allowed us to measure quantal amplitude and kinetic data in order to evaluate postsynaptic strength pertaining to the particular synapses under investigation (Oliet et al. 1996).”

“Second, we obtained quantal size estimates in both cortical and thalamic inputs by measuring the amplitude of asynchronously released single quanta of glutamate when strontium (Sr) was substituted for extracellular Ca (Oliet et al., 1996).”

“To test the former possibility, we examined the amplitude and time course of mEPSCs, which were evoked from CFs after replacing extracellular Ca 2 with Sr 2 (Miledi, 1966; Oliet et al., 1996; Xu-Friedman and Regehr, 2000).”

“…in which extracellular Ca2 was replaced with 4 mM Sr2 to cause asynchronous release of glutamate from axonal terminals, thereby resulting in aEPSCs, the unitary events comprising synchronous EPSCs evoked at a normal calcium concentration (Oliet et al., 1996; Xu-Friedman and Regehr, 2000).”

“When Ca is replaced with Sr, synchronous transmitter release is replaced by asynchronous release, which lasts for a few hundredmilliseconds after the stimulus (Miledi, 1966;Oliet et al., 1996;Xu-Friedmanand Regehr, 2000).”

“We therefore replaced all calcium (2 mM) in the extracellular medium with strontium (2 mM), a change that alters evoked synaptic release from smoothly synchronous to largely asynchronous, with quantal stimulated strontium EPSCs (SrEPSCs) strung out individually over a window of a few hundred milliseconds after stimula…”

“We next measured the effects of CCK on the quantal properties of glutamate release at the PP-GC synapses using the method of replacing extracellular Ca 2 with strontium (Sr 2 ) to induce asynchronous transmitter release (Goda and Stevens, 1994; Oliet et al., 1996).”

“We replaced Ca in the extracellular solution with Sr, which enters the presynaptic terminal through calcium channels and triggers neurotransmitter release, albeit with lower efficiency (Bekkers and Clements, 1999; Oliet et al., 1996).”

“Asynchronous EPSCs may be observed for hundreds of milliseconds following the presynaptic stimulation pulse, thus permitting analysis of quantal responses in specific projections to the target area (36).”

“In contrast to conventional mEPSC recordings, which are based on a stochastic release of presynaptic vesicles, asynchronous EPSCs (aEPSCs) are induced by local electrical stimulation and can thus be attributed to the stimulated afferents [37,38].”

“contrarily to the event observed in LTP (Manabe et al., 1992; Oliet et al., 1996).”

“The AMPA-mediated component of the excitatory postsynaptic current (EPSC) is selectively increased after induction of LTP (20) and dramatically decreased after induction of LTD (21).”

“The importance of this finding may be considerable, since theoretical reports and empirical data indicate that synaptic function is regulated by the interaction of LTP and LTD mechanisms (Hrabetva & Saktor, 1996; Mayford, Wang, Kandel, & O’Dell, 1995; Oliet, Malenka, & Nicoll, 1996; Oliet, Malenka, & Nicoll, 1997).”

“Ethanol Alters the Frequency, Amplitude, and Decay Kinetics of Sr2 - Supported, Asynchronous NMDAR mEPSCs in Rat Hippocampal Slices”

“, 2010), for example, might contribute to the mechanisms underling LTD expression (Oliet et al., 1996; Beattie et al., 2000).”