Graded bidirectional synaptic plasticity is composed of switch-like unitary events

Abstract

Biological information storage events are often rapid transitions between discrete states. In neural systems, the initiation of bidirectional plasticity by all-or-none events may help confer robustness on memory storage. Here, we report that at CA3-CA1 hippocampal synapses, individual potentiation and depression plasticity events are discrete and heterogeneous in nature. Individual synapses began from extreme high and low strength states. Unitary plasticity events were all-or-none and drove synaptic strength between extremes in <1 min. Under naïve conditions, approximately three-fourths of synapses began in a low-strength state. The timing of these unitary events can account for the time course of macroscopic synaptic plasticity.B oth increases (long-term potentiation, LTP) (1) and decreases (long-term depression, LTD) in synaptic strength are almost always measured macroscopically across populations of synaptic contacts (2). Macroscopic recordings, in which plasticity appears as a graded phenomenon, have ranged from extracellular recordings from many thousands of synapses (3, 4) to single-cell recordings (5), including recordings from connected pairs of nearby single neurons representing summed activity from order 10 synaptic terminals (6, 7).Plasticity has been described in terms of transitions among distinct states (7). However, the concept of synaptic states has not been explored in terms of unitary synaptic strength. Characterizing plasticity at this level requires observations from putative single terminals.An attractive system for studying unitary plasticity events is the hippocampal CA3-CA1 pathway (4, 8), where connected CA3 and CA1 neurons communicate typically by a single synaptic contact (9). Minimal stimulation techniques (10-12) allow plasticity transitions to be localized in time as they occur (13). Previous work (13) indicates that unitary synaptic potentiation, at least in its initial stages, may be an all-or-none event.Here, we report on the unitary properties of the initiation of potentiation and depression at CA3-CA1 synapses. We find that both potentiation and depression events are all-or-none and sudden. These events can be reconstituted to account for the time course of plasticity on a macroscopic scale. MethodsSlice Preparation. Transverse hippocampal slices (300 m) from Sprague-Dawley rats (postnatal day 13-21) were cut in ice-cold artificial cerebrospinal fluid (ACSF) comprising (in mM) 126 NaCl, 3 KCl, 1 NaH 2 PO 4 , 25 D-glucose, 25 NaHCO 3 , 2 CaCl 2 , and 1 MgCl 2 saturated with 95% O 2 ͞5% CO 2 , incubated at 34°C for 10-15 min, and transferred to a room-temperature interface chamber for Ն60 min before recording. The cutting angle was such that excitatory postsynaptic current (EPSC) size in response to stimulation of stratum radiatum decreased rapidly as the stimulation electrode was moved toward CA3. By using this cutting angle and moving the stimulation electrode as far toward CA3 as possible, we reduced the likelihood of stimulating multiple connected axons. For recordings, slic...

Calcium control of triphasic hippocampal STDP

“…Similar results have been obtained at excitatory connections between cortical pyramidal neurons [35]. Other experimental data indicates that potentiation and depression events are switch-like transitions between binary conductance states, mediated by kinase and phosphotase pathways that are co-activated and competitive [36][37][38][39][40]. The kinetics of kinase and phosphotase activation also differ significantly, as LTP can be rapidly induced by appropriate patterns of activity while LTD requires prolonged stimulation [15,17,29].…”

“…It is also interesting to note that, due to the higher gain and shorter time constant governing kinase activation, transitions between low and high weight states induced by potentiating stimuli take consistently less time than transitions between high and low weight states induced by depressing stimuli (69±50s at ∆t=15ms and 108±55s at ∆t=-15ms for 5Hz Triplet pairing, for example), and each is on a similar timescale to that observed experimentally (80±70s for LTP and 183±126s for LTD in O'Connor, Wittenberg and Wang [37]; 38s for LTP in Bagal et al [39]). …”

“…It has been demonstrated that changes in AMPAr conductance associated with the expression of long-term synaptic plasticity are accompanied by concomitant changes in NMDAr conductance [69,76]. This has interesting implications for further synaptic plasticity -as both the level of depolarisation in the spine and the level of NMDAr-dependent Calcium influx generated by that depolarisation will be concurrently modulated, possibly contributing to the 'lock-in' of changes in synaptic conductance observed experimentally [37].…”

“…Equilibrium values are subsequently set such that the relative occupation of high and low weight states at rest corresponds to that observed experimentally, f P0 =79% of synapses occupying the low weight state and f D0 =21% occupying the high weight state at the start of each simulation [37]. In line with empirical measurements regarding the relative conductance of potentiated and depressed CA3-CA1 synapses, we set the relative strength of high and low weight states as w P =2 and w D =0.66 respectively [REFS].…”

Malleability of Spike-Timing-Dependent Plasticity at the CA3-CA1 Synapse

“…Cells were held in voltage clamp at Ϫ70 mV except for eight recordings done in current clamp. EPSCs were evoked either every 10 or 30 s. The stimulation intensity was adjusted until EPSC responses on screen were judged to be between 50 and 150 pA (92 Ϯ 36 pA, mean Ϯ SD), of order 10 times as large as unitary CA3-CA1 synaptic strength (O'Connor et al, 2005a). Based on a 5 mV hyperpolarizing voltage test step during each sweep, the input resistance was 190 Ϯ 49 M⍀ (mean Ϯ SD), and the series resistance, which was not compensated in voltage clamp recordings, was 32 Ϯ 16 M⍀ (mean Ϯ SD).…”