Depolarization-Induced Long-Term Depression at Hippocampal Mossy Fiber-CA3 Pyramidal Neuron Synapses

Abstract

Hippocampal CA3 pyramidal neurons receive two types of excitatory afferent innervation: mossy fibers (MFs) from granule cells of the dentate gyrus and recurrent collateral fibers (CFs) from other CA3 pyramidal neurons. At CF-CA3 pyramidal neuron synapses, membrane depolarization paired with low (0.33 Hz) presynaptic stimulation generated a heterogeneous response that ranged from long-term potentiation (LTP), long-term depression (LTD), to no alteration of synaptic strength. However, the same induction paradigm applied at MF-CA3 pyramidal neuron synapses consistently induced LTD. This novel form of LTD was independent of NMDARs, mGluRs, cannabinoid receptors, opioid receptors, or coincident synaptic activity, but was dependent on postsynaptic Ca2+ elevation through L-type Ca2+ channels and release from inositol 1,4,5-trisphosphate receptor-sensitive intracellular stores. Ca2+ imaging of both proximal and distal CA3 pyramidal neuron dendrites demonstrated that the depolarizing induction paradigm differentially elevated intracellular Ca2+ levels. L-type Ca2+ channel activation was observed only at the most proximal locations where mossy fibers make synapses. Depolarization-induced LTD did not occlude the conventional 1 Hz-induced LTD or vice versa, suggesting independent mechanisms underlie each form of plasticity. The paired-pulse ratio and coefficient of variation of synaptic transmission were unchanged after LTD induction, suggesting that the expression locus of LTD is postsynaptic. Moreover, peak-scaled nonstationary variance analysis indicated that depolarization-induced LTD correlated with a reduction in postsynaptic AMPA receptor numbers without a change in AMPA receptor conductance. Our results suggest that this novel form of LTD is selectively expressed at proximal dendritic locations closely associated with L-type Ca2+ channels.