Abstract
The GluA2 subunit of AMPA glutamate receptors (AMPARs) has been shown to be critical for the expression of NMDA receptor (NMDAR)-dependent long-term depression (LTD). However, in young GluA2 knockout (KO) mice, this form of LTD can still be induced in the hippocampus, suggesting that LTD mechanisms may be modified in the presence of GluA2-lacking, Ca2+ permeable AMPARs. In this study, we examined LTD at the CA1 synapse in GluA2 KO mice by using several well-established inhibitory peptides known to block LTD in wild type (WT) rodents. We showed that while LTD in the KO mice is still blocked by the protein interacting with C kinase 1 (PICK1) peptide pepEVKI, it becomes insensitive to the N-ethylmaleimide-sensitive factor (NSF) peptide pep2m. In addition, the effects of actin and cofilin inhibitory peptides were also altered. These results indicate that in the absence of GluA2, LTD expression mechanisms are different from those in WT animals, suggesting that there are multiple molecular processes enabling LTD expression that are adaptable to physiological and genetic manipulations.
Highlights
In the mammalian CNS, AMPA glutamate receptors (AMPARs) are the principal mediators of fast excitatory synaptic transmission and they are important in the expression of various forms of long-lasting synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD; Malinow and Malenka, 2002; Bredt and Nicoll, 2003; Shepherd and Huganir, 2007; Collingridge et al, 2010; Huganir and Nicoll, 2013; Henley and Wilkinson, 2016)
D, this form of LTD was induced in both young wild type (WT) and KO mice (Figure 2C, WT: 78.2 ± 3.9%, n = 5; KO: 73.5 ± 5.2%, n = 9; p > 0.05) and mature WT mice (Figure 2D, WT: 70.7 ± 1.9%, n = 5), it was absent in mature KO mice (Figure 2D, KO: 104.2 ± 5.2%, n = 7; p < 0.05). These results indicate that GluA2 is required for both NMDA receptors (NMDARs)- and mGluR-LTD in mature, but not in young mice
LTD is impaired in mature GluA2 KO mice, it can be restored by manipulating N-ethylmaleimide-sensitive factor (NSF) or cofilin, suggesting that the basic machinery for LTD expression is still present in these KO mice
Summary
In the mammalian CNS, AMPA glutamate receptors (AMPARs) are the principal mediators of fast excitatory synaptic transmission and they are important in the expression of various forms of long-lasting synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD; Malinow and Malenka, 2002; Bredt and Nicoll, 2003; Shepherd and Huganir, 2007; Collingridge et al, 2010; Huganir and Nicoll, 2013; Henley and Wilkinson, 2016). AMPARs are heteromeric complexes assembled from four distinct subunits, GluA1–4; in most principal neurons, AMPARs contain the GluA2 subunit (Wenthold et al, 1996; Isaac et al, 2007; Lu et al, 2009). The inclusion of GluA2 in the receptor complex confers a number of key properties of AMPARs, including Ca2+ permeability, receptor assembly and trafficking (Isaac et al, 2007). Genetic and molecular ablation of GluA2 result in severe impairments in AMPAR assembly, synaptic physiology and behavior (Jia et al, 1996; Gerlai et al, 1998; Yan et al, 2002; Sans et al, 2003; Toyoda et al, 2007; Kessels and Malinow, 2009).
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