Abstract
Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of long-lasting synaptic plasticity widely regarded as the cellular basis for learning and memory. At the CA1 synapse, there are multiple forms of LTP with distinct properties. Although AMPA glutamate receptors (AMPARs) are a key target of LTP expression, whether they are required in all forms of LTP remains unclear. To address this question, we have used our recently developed mouse line, GluA1C2KI, where the c-terminal domain (CTD) of the endogenous GluA1 is replaced by that of GluA2. Unlike traditional GluA1 global or conditional KO mice, GluA1C2KI mice have no changes in basal AMPAR properties or synaptic transmission allowing a better assessment of GluA1 in synaptic plasticity. We previously showed that these mice are impaired in LTP induced by high-frequency stimulation (HFS-LTP), but whether other forms of LTP are also affected in these mice is unknown. In this study, we compared various forms of LTP at CA1 synapses between GluA1C2KI and wild-type littermates by using several induction protocols. We show that HFS-LTP is impaired in both juvenile and adult GluA1C2KI mice. The LTP induced by theta-burst stimulation (TBS-LTP) is also abolished in juvenile GluA1C2KI mice. Interestingly, TBS-LTP can still be induced in adult GluA1C2KI mice, but its mechanisms are altered becoming more sensitive to protein synthesis and the extracellular signal-regulated kinase (ERK) inhibitors compared to wild type (WT) control. The GluA1C2KI mice are also differentially altered in several forms of LTP induced under whole-cell recording paradigms. These results indicate that the CTD of GluA1 is differentially involved in different forms of LTP at CA1 synapse highlighting the complexity and adaptative potential of LTP expression mechanisms in the hippocampus.
Highlights
Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of synaptic plasticity widely regarded as key mechanisms for learning and memory (Bliss and Collingridge, 1993; Malenka and Bear, 2004; Kandel et al, 2014)
We have shown that GluA1C2KI mice showed no impairments in AMPA receptors (AMPARs) properties or long-term depression (LTD), but impairments in NMDA receptors (NMDARs)-LTP induced by high-frequency stimulation (HFS, 100 Hz) in the hippocampal CA1 synapses
theta-burst stimulation (TBS) induced LTP in wild type (WT) mice, but not in GluA1C2KI mice (Figure 1B). These results indicate that in juvenile mice the C-TERMINAL DOMAIN (CTD) of GluA1 is indispensable for both HFS- and TBS-LTP
Summary
Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of synaptic plasticity widely regarded as key mechanisms for learning and memory (Bliss and Collingridge, 1993; Malenka and Bear, 2004; Kandel et al, 2014). LTP has been most intensively investigated at the Schaffer collateral-commissural projection between CA3 and CA1 pyramidal neurons of the hippocampus. At these synapses, NMDA receptor-dependent LTP (NMDAR-LTP) is triggered by the activation of NMDARs and subsequent Ca2+ influx into the postsynaptic spine (Collingridge et al, 1983; Bliss and Collingridge, 1993). Many studies have shown that the trafficking of AMPA receptors (AMPARs) represents a key mechanism in the expression of LTP (Davies et al, 1989; Malinow and Malenka, 2002; Bredt and Nicoll, 2003; Collingridge et al, 2004; Malenka and Bear, 2004; Shepherd and Huganir, 2007; Kessels and Malinow, 2009; Anggono and Huganir, 2012; Henley and Wilkinson, 2016; Diering and Huganir, 2018). In vitro studies using recombinant receptors and peptides have shown that the C-TERMINAL DOMAIN (CTD) of GluA1, but not of GluA2, is required for activity-dependent synaptic delivery of AMPARs and expression of LTP (Hayashi et al, 2000; Shi et al, 1999, 2001; Boehm et al, 2006; Kessels and Malinow, 2009)
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