Abstract
Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre–post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post–pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post–pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post–pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.
Highlights
Spike timing-dependent plasticity (STDP) is a Hebbian synaptic learning rule that may underlie neural circuit remodeling and behavioral adaptations (Bi and Poo, 2001; Dan and Poo, 2006; Caporale and Dan, 2008; Feldman, 2012; Ganguly and Poo, 2013)
Induction of Hebbian STDP depends on postsynaptic N -methyl-D-aspartate receptors (NMDARs), a classical coincidence detector of presynaptic and postsynaptic discharges and a source of intracellular Ca2+ influx needed for synaptic modifications (Caporale and Dan, 2008; Feldman, 2012)
Our results indicate that DA drives t-LTP at −30 ms, enabling a form of anti-Hebbian t-LTP that depends on postsynaptic D1-cAMP/PKA signaling and GluN2B-containing NMDARs in pyramidal neurons
Summary
Spike timing-dependent plasticity (STDP) is a Hebbian synaptic learning rule that may underlie neural circuit remodeling and behavioral adaptations (Bi and Poo, 2001; Dan and Poo, 2006; Caporale and Dan, 2008; Feldman, 2012; Ganguly and Poo, 2013). Opposite to classical Hebbian STDP, atypical forms of STDP have been observed at some synapses, where pre–post spikings drive t-LTD and post–pre spikings drive t-LTP (Han et al, 2000; Fino et al, 2005; Safo and Regehr, 2005; Letzkus et al, 2006; Lu et al, 2007; Fino et al, 2008) These STDP variants, referred as anti-Hebbian, are relatively rare and often depend on NMDARs, anti-Hebbian t-LTP (Letzkus et al, 2006)
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