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1.  Preynaptic induction and expression of t-LTD demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist 
N-methyl-d-aspartate (NMDA) receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). In order to help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist, MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. To demonstrate the potential of this new method, we investigated timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use-dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses.
PMCID: PMC4299820  PMID: 21653860
Mouse; barrel cortex; LTD; NMDA; MK801; photolysis
2.  Distinct mechanisms of spike timing‐dependent LTD at vertical and horizontal inputs onto L2/3 pyramidal neurons in mouse barrel cortex 
Physiological Reports  2014;2(3):e00271.
Spike timing‐dependent plasticity (STDP) is an attractive candidate to mediate the synaptic changes that support circuit plasticity in sensory cortices during development. STDP is prevalent at excitatory synapses, but it is not known whether the underlying mechanisms are universal, or whether distinct mechanisms underpin STDP at different synapses. Here, we set out to compare and contrast STDP at vertical layer 4 and horizontal layer 2/3 inputs onto postsynaptic layer 2/3 neurons in the mouse barrel cortex. We find that both vertical and horizontal inputs show STDP, but that they display different time windows for induction of timing‐dependent long‐term depression (t‐LTD). Moreover, whereas t‐LTD at vertical inputs requires presynaptic NMDA receptors and is expressed presynaptically, using paired recordings we find that t‐LTD at horizontal inputs requires postsynaptic NMDA receptors and is expressed postsynaptically. These results demonstrate that similar forms of plasticity on the same postsynaptic neuron can be mediated by distinct mechanisms, and suggest that these forms of plasticity may enable these two types of cortical synapses to support different functions.
Timing‐dependent LTD (t‐LTD) at vertical inputs on layer 2/3 neurons (L4‐L2/3) requires presynaptic NMDA receptors and is expressed presynaptically, but little is known about these mechanisms at horizontal inputs (L2/3‐L2/3). Using paired recordings we demonstrate here that t‐LTD at L2/3‐L2/3 synapses also requires NMDA receptors but is induced and expressed postsynaptically. These results indicate that similar forms of plasticity on the same postsynaptic neuron may be mediated by distinct mechanisms and suggest that these forms of plasticity may support different developmental functions in the cortex.
PMCID: PMC4002250  PMID: 24760524
LTD; LTP; mouse; somatosensory cortex; STDP
3.  Presynaptic Self-Depression at Developing Neocortical Synapses 
Neuron  2013;77(1):35-42.
A central tenet of most theories of synaptic modification during cortical development is that correlated activity drives plasticity in synaptically connected neurons. Unexpectedly, however, using sensory-evoked activity patterns recorded from the developing mouse cortex in vivo, the synaptic learning rule that we uncover here relies solely on the presynaptic neuron. A burst of three presynaptic spikes followed, within a restricted time window, by a single presynaptic spike induces robust long-term depression (LTD) at developing layer 4 to layer 2/3 synapses. This presynaptic spike pattern-dependent LTD (p-LTD) can be induced by individual presynaptic layer 4 cells, requires presynaptic NMDA receptors and calcineurin, and is expressed presynaptically. However, in contrast to spike timing-dependent LTD, p-LTD is independent of postsynaptic and astroglial signaling. This spike pattern-dependent learning rule complements timing-based rules and is likely to play a role in the pruning of synaptic input during cortical development.
► Natural spike patterns in layer 4 neurons induce LTD at downstream synapses ► Spike pattern-dependent LTD can be induced in individual presynaptic neurons ► Spike pattern-dependent LTD requires presynaptic NMDA receptors and calcineurin ► Spike pattern-dependent LTD is independent of postsynaptic and astroglial signaling
Using natural spike patterns recorded from cortical layer 4 neurons in vivo, Rodríguez-Moreno et al. uncover a new spike pattern-dependent synaptic learning rule. They find that individual presynaptic neurons can drive NMDA receptor-dependent synaptic depression without a requirement for postsynaptic activity.
PMCID: PMC3542421  PMID: 23312514
4.  Caged intracellular NMDA receptor blockers for the study of subcellular ion channel function 
We have previously synthesized a caged form of the use-dependent N-methyl-D-aspartate (NMDA) receptor ion channel blocker MK801 and used intracellular photolysis of this compound to demonstrate the subcellular location of NMDA receptor ion channels involved in synaptic plasticity. Here, we discuss considerations regarding the choice of caging molecule, synthesis and the potential uses for caged ion channel blockers in neurophysiology.
PMCID: PMC3419105  PMID: 22896783
NMDA; MK801; ion channel; cage; photolysis
5.  Presynaptic NMDA Receptors and Spike Timing-Dependent Depression at Cortical Synapses 
It has recently been discovered that some forms of timing-dependent long-term depression (t-LTD) require presynaptic N-methyl-d-aspartate (NMDA) receptors. In this review, we discuss the evidence for the presence of presynaptic NMDA receptors at cortical synapses and their possible role in the induction of t-LTD. Two basic models emerge for the induction of t-LTD at cortical synapses. In one model, coincident activation of presynaptic NMDA receptors and CB1 receptors mediates t-LTD. In a second model, CB1 receptors are not necessary, and the activation of presynaptic NMDA receptors alone appears to be sufficient for the induction of t-LTD.
PMCID: PMC3059699  PMID: 21423504
plasticity; STDP; t-LTD; NMDA; presynaptic mechanisms
6.  Double Dissociation of Spike Timing–Dependent Potentiation and Depression by Subunit-Preferring NMDA Receptor Antagonists in Mouse Barrel Cortex 
Cerebral Cortex (New York, NY)  2009;19(12):2959-2969.
Spike timing–dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit–containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit–preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.
PMCID: PMC2774397  PMID: 19363149
development; LTD; LTP; rodent; synaptic plasticity

Results 1-6 (6)