The Role of Calcium-Permeable AMPARs in Long-Term Potentiation at Principal Neurons in the Rodent Hippocampus

Abstract

Long-term potentiation (LTP) at hippocampal CA1 synapses is classically triggered by the synaptic activation of NMDA receptors (NMDARs). More recently, it has been shown that calcium-permeable (CP) AMPA receptors (AMPARs) can also trigger synaptic plasticity at these synapses. Here, we review this literature with a focus on recent evidence that CP-AMPARs are critical for the induction of the protein kinase A (PKA)- and protein synthesis-dependent component of LTP.

Keywords: NMDA receptor; PKA; calcium-permeable AMPA receptor; hippocampus; long-term potentiation.

Figure 1

Calcium-permeable (CP)-AMPA receptors (AMPARs) can trigger long-term potentiation (LTP) at CA1 synapses. (A) Larger LTP in GluA2^−/– mice compared with wild-type littermates. (B) NMDA receptors (NMDARs)-independent LTP in the GluA2^−/– mice. (C) Acute restraint stress facilitates LTP. (D) Acute restraint stress enables NMDAR-independent LTP. Panels (A,B) from Jia et al. (1996) and (C,D) from Whitehead et al. (2013).

Figure 2

LTP2, but not LTP1, is sensitive to CP-AMPAR blockers. (A) Philanthotoxin (PhTx) reverses the potentiation when applied starting 10 min after pairing-induced LTP. (B) PhTx has no effect when applied starting 20 min after the induction of LTP. (C) LTP is not induced when baseline stimulation is paused for 15 min following pairing (from Plant et al., 2006). (D) IEM 1460 (30 μM) has no effect on LTP induced by compressed protocol (cTBS; n = 8 and 6 for vehicle and IEM experiments, respectively). (E) IEM 1460 applied immediately following the first theta burst stimulation (TBS) inhibits LTP. (F) IEM 1460 applied 1 h following the last spaced protocol (sTBS) has no effect on LTP. (G) Summary data (n = 6–10 for IEM experiments, n = 21 for interleaved controls). Each graph plots the mean ± SEM normalized fEPSP slope for vehicle-treated (black) and interleaved drug-treated (color) slices. The open symbols are the corresponding control (no TBS) inputs. Representative traces (average of five successive recordings) are shown for the times indicated by numbers. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. control. Reproduced from Park et al. (2016).

Figure 3

Stimulation post-TBS is required for LTP2. (A) Baseline stimulation was paused following the second and third sTBS episodes (apart from an initial stimulation to assess short-term potentiation, STP) for nine experiments. (B) Interleaved control experiments where there was no pause in stimulation (n = 7). (C) Representative traces (at the times indicated by numbers). (D) Quantification of these experiments (2 h post TBS). Reproduced from Park et al. (2016). **p < 0.01 vs. control.

Figure 4

A scheme to explain how CP-AMPARs may trigger LTP2. (A) Baseline conditions. The synaptic complement comprises NMDARs (predominantly GluN1/GluN2A/GluN2B) and calcium impermeable (CI)-AMPARs (note only one of each receptor type is shown for simplicity). (B,C) The first TBS (or cTBS, cHFS, etc.) induces LTP1 via activation of CaMKII and involves the synaptic insertion of additional CI-AMPARs. (D) The first TBS also drives CP-AMPARs into the perisynaptic plasma membrane, via a pathway involving protein kinase A (PKA). (E) Additional TBS activates NMDARs to drive CP-AMPARs from the perisynaptic to the synaptic membrane. (F) Baseline stimulation leads to Ca²⁺ entry via CP-AMPARs, which triggers de novo protein synthesis (via PI3K and MAPK). (G) Consequently, what follows is spine growth and the incorporation of additional CI-AMPARs. CP-AMPARs are removed from the synapse around the same time.