Abstract
Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12–P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca2+ for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca2+ release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.
Highlights
One of the most interesting properties of the mammalian brain is its ability to change in response to experience
We monitored excitatory postsynaptic potentials (EPSPs) evoked by extracellular stimulation in the stratum radiatum during wholecell recording of CA1 pyramidal cells in slices prepared from the mouse hippocampus as previously described (Meredith et al 2003; Kwag and Paulsen 2012). timing-dependent long-term potentiation (t-long-term potentiation (LTP)) and timing-dependent long-term depression (t-long-term depression (LTD)) were induced in current clamp using 100 pairings of single EPSPs and single postsynaptic spikes at 0.2 Hz
In slices treated with the NMDA receptor antagonist -2-amino5-phosphonopentanoic acid ( -AP5), a pre-before-post pairing protocol failed to induce t-LTP (102 ± 7%, n = 5; vs. interleaved controls, 143 ± 7%, n = 5; Fig. 2D,F). -AP5 blocked t-LTD; in -AP5-treated slices, a post-before-pre pairing protocol did not induce t-LTD (110 ± 7%, n = 7 vs. interleaved controls, 71 ± 8%, n = 5; Fig. 2E,F). These results indicate that both t-LTP and t-LTD require NMDA receptors
Summary
One of the most interesting properties of the mammalian brain is its ability to change in response to experience This property was termed plasticity by the Spanish neuroscientist Santiago Ramón y Cajal more than a century ago (Cajal 1894). The most extensively studied forms of plasticity are long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. Spike timing-dependent plasticity (STDP) is a Hebbian form of long-term synaptic plasticity found in all species studied, from insects to humans, and is a strong candidate for a synaptic mechanism underlying circuit remodeling during development as well as learning and memory (Feldman and Brecht 2005; Dan and Poo 2006; Caporale and Dan 2008; Feldman 2012). Whereas the mechanisms of STDP have been extensively studied at neocortical synapses (Sjöström et al 2003; Bender et al 2006; Rodríguez-Moreno and Paulsen 2008; Rodríguez-Moreno et al 2011, 2013), comparatively less is known about STDP at hippocampal synapses
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