NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD)

Abstract

Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory.

Figure 1.

NMDAR-dependent LTD and LTP in the hippocampus. (A) Historical drawing by Ramon y Cajal (1909) of the trisynaptic pathway in the hippocampus. LTP and LTD are induced by activation of NMDARs at synapses between CA3 and CA1 pyramidal neurons (blue and red). In contrast, LTP at mossy fiber synapses onto CA3 neurons (green on blue) is NMDAR-independent. (B) This electron microscopy image shows the densely packed neuropil in the CA1 region of the hippocampus and highlights two asymmetric CA3-CA1 synapses. Note the typical “bouton en passant” configuration of synapse 1 and the prominent spine in synapse 2. The postsynaptic densities (PSDs) are visible. Scale bar, 200 nm. (Image kindly provided by Rafael Luján, Universitad de Castilla-La Mancha.) (C) Bidirectional change in CA3-CA1 synaptic efficacy by LTD and LTP in the same synapses monitored by extracellular field recordings in an acute slice preparation of the hippocampus. Note the contrasting induction protocols (Data from C Lüscher, unpubl.).

Figure 2.

Major ionotropic glutamate receptors involved in LTD and LTP. (A) When glutamate binds to AMPA receptors, many sodium ions flow into the cell while only some potassium ions leave the neuron, causing a net depolarization of the membrane. NMDA receptors are also permeable for calcium but only if the magnesium is expelled by a slight depolarization of the neuron. (B) The current–voltage (I–V) relationship provides a biophysical signature for the different receptors. AMPA receptors have a linear I–V relationship when they contain the subunit GluA2, but are inward-rectifying (see text for definition) without GluA2. NMDA receptors have a complex I–V curve because Mg blocks the pore at negative potentials.

Figure 3.

Postsynaptic expression mechanisms of LTP and LTD. (A) Weak activity of the presynaptic neuron leads to modest depolarization and calcium influx through NMDA receptors. This preferentially activates phosphatases that dephosphorylate AMPA receptors, thus promoting receptor endocytosis. Strong activity paired with strong depolarization triggers LTP in part via CaMKII, receptor phosphorylation, and exocytosis. (B) When endocytosis is blocked with a dynamin dominant-negative peptide, LTD is inhibited. Conversely, blocking exocytosis abolishes LTP. (Left panel: adapted and reprinted, with permission, from Lüscher et al. 1999; right panel: W Morishita and RC Malenka, unpubl.)

Figure 4.

Structural changes associated with LTP and LTD. (A) Synaptic strength correlates with spine volume and the area of the postsynaptic density (orange). Note that the PSD in potentiated synapses is often perforated. (B) LTP can also lead to the appearance of new spines. Within 30 min of triggering LTP (30 stimuli applied to the presynaptic axon at 10-sec intervals paired with depolarizing current injection into the postsynaptic neuron; black bar) of a synaptic connection in the hippocampus, new spines appear. (Panel created from data adapted from Engert and Bonhoeffer 1999.)

Figure 5.

Block of LTP and triggering of LTD by Aβ oligomers in Alzheimer’s disease (AD). Soluble Aβ oligomers strongly activate metabotropic glutamate receptors (mGluRs), which leads to the internalization of AMPARs and LTD. As a consequence, normal NMDAR-dependent LTD is occluded. At the same time they inhibit NMDARs, precluding the induction of LTP. In a second step synapses become thinner and some disappear. It is believed that these changes underlie the early cognitive decline observed in AD.