Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Abstract

SUMMARY Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses.

Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses

“…In addition, it remains possible that other postsynaptic mechanisms, such as altered receptor desensitization, may be altered by SRE and could contribute to the apparent change in release measured by PPR. However, our results are consistent with other studies that show presynaptic NMDARs can regulate release, and are regulated by sensory-evoked activity Rodríguez-Moreno and Paulsen 2008;Kunz et al 2013;Larsen et al 2014).…”

“…The NR2B (GluN2B/Grin2b) subunit has been associated with long-term depression (Liu et al 2004;Massey et al 2004) but see Hrabetova et al (2000) and Yoshimura et al (2003), and activity-dependent up-regulation of presynaptic NR2B and NR3A (GluN3A/Grin3a) has been observed at some neocortical synapses (Yang et al 2006;Larsen et al 2014). Typically, NR2B is more prevalent during early development, and is replaced with NR2A in older animals.…”

Optogenetics: 10 years of microbial opsins in neuroscience

“…Learning itself has been studied with optogenetics in ventral striatum and amygdala 143,144 , as well as in the hippocampus 138 , and inputs to the hippocampal formation have been studied in some detail with regard to causal roles in learning, navigation and information flow 145–147 . Finally, precisely timed activity patterns in diverse well-defined cell types, projections and populations have been causally implicated in synaptic plasticity 148,149 , wiring and microcircuit plasticity 150,151 , and in long-timescale devel-opmental 152,153 and adaptive changes such as activity-dependent myelination 154 and adult neurogenesis 155,156 .…”

Closing the gap: long-term presynaptic plasticity in brain function and disease

“…Likely acting as coincidence detectors, preNMDARs contribute to presynaptic spike-timing dependent (STDP) forms of LTD (a.k.a. tLTD) wherein action potentials in close precession of excitatory postsynaptic potentials result in eCB-LTD particularly at synapses in juvenile animals [14, 17–19]. In Xenopus optic tectum, activation of preNMDARs by glutamate release from nearby excitatory synapses triggers presumably eCB-independent LTD of GABA release [20].…”