Increased expression, but not postsynaptic localisation, of ionotropic glutamate receptors during the late-phase of long-term potentiation in the dentate gyrus in vivo
Introduction
Long-term potentiation (LTP) is an activity-dependent increase in synaptic efficacy that is widely studied as a mechanism underlying information storage. The key properties of LTP, i.e. input specificity, associativity and particularly its considerable persistence, make it useful as a mnemonic device (Lynch, 2004). While activation and modification of ionotropic glutamate receptors are important mediators of early-phase LTP (Malenka and Bear, 2004), little is known about how early-phase LTP progresses to forms that last for days or longer (Abraham et al., 2002). This is a significant knowledge gap, since an understanding of the mechanisms of LTP maintenance is likely to be critical for understanding the molecular mechanisms of memory retention.
In the early-phase of LTP in vitro, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are rapidly inserted into postsynaptic membranes (Hayashi et al., 2000, Shi et al., 2001). Similarly, postsynaptic membrane recruitment of N-methyl-d-aspartate receptors (NMDARs) and AMPARs occurs during the early-phase of perforant path LTP in vivo (Williams et al., 2007). Presynaptic mechanisms may also contribute to the early expression of LTP in vitro (Emptage et al., 2003) and in vivo (Errington et al., 2003, Lynch et al., 1994), suggesting that the expression of early-phase LTP involves a complex reorganisation of synapses.
Although persistent activation of protein kinases plays a role in LTP maintenance (Fukunaga et al., 1993, Pastalkova et al., 2006, Sanhueza et al., 2007), long-term maintenance of LTP in vivo also requires de novo protein synthesis (Abraham and Williams, 2008, Otani et al., 1989). We have previously shown that late-phase LTP in the dentate gyrus in vivo is associated with elevated levels of NMDAR complex proteins 2 days after LTP induction (Williams et al., 1998, Williams et al., 2003). However, while enhanced NMDAR currents contribute to future bouts of synaptic potentiation (Watt et al., 2004), modulation of AMPAR transmission is the focal point for the expression of LTP. Increased expression of AMPAR subunits has been reported hours after LTP induction both in acute hippocampal slices (Nayak et al., 1998), and in area CA1 in vivo (Heynen et al., 2000), but it is yet to be determined how these changes contribute to LTP maintenance or if they persist over the course of days after LTP induction. Our finding of increased synaptic NMDAR expression (Williams et al., 2003), alongside LTP-associated synaptic reorganisation (e.g. Matsuzaki et al., 2004) suggests that LTP maintenance is associated with an increase in synaptic contact area. Furthermore, as PSD95 expression is increased in synaptic fractions during the LTP late-phase (Williams et al., 2003) this suggests that synaptic AMPAR localisation may be increased (Ehrlich and Malinow, 2004). Accordingly, this study investigated whether there are long-term, NMDAR-dependent increases in expression of AMPAR subunits in the dentate gyrus during late-phase perforant path LTP. In addition, we investigated whether any changes could be localised to the synaptic surface membranes or to the postsynaptic density. Some of the data presented here have been published previously in abstract form (Kennard et al., 2005).
Section snippets
Methods
All experiments were conducted on perforant path-dentate gyrus synapses in adult male Sprague-Dawley rats (400–550 g, 4–6 months old at the time of surgery), using surgical protocols approved by the University of Otago Animal Ethics Committee and in accord with New Zealand animal welfare legislation. Animals were anaesthetised with pentobarbital (60 mg/kg, i.p.). The surgery protocols and the placement of electrodes for electrophysiological analysis of perforant path-evoked field excitatory
GluA1 and GluA2 subunit expression is increased 48 h after LTP induction
Previously, we have reported that the late-phase of perforant path LTP is associated with increased levels of NMDAR subunits and associated proteins in the dentate gyrus (Williams et al., 1998, Williams et al., 2003). To determine whether these increases are specific to the NMDAR complex or representative of a more generalised response we have assessed in the present experiment whether AMPAR subunit levels are also altered in the dentate gyrus following the late-phase of LTP in vivo.
HFS of
Discussion
We have shown that 48 h after the induction of perforant path-dentate LTP in vivo there is an up-regulation in the overall levels of the AMPAR subunits GluA1 and GluA2, consistent with our previous findings of increased NR subunits at this time-point (Williams et al., 2003). However, unlike at earlier time-points (Williams et al., 2007), this AMPAR subunit expression is not reflected in an increase in either synaptic surface membrane or PSD expression. We also examined the subcellular
Acknowledgements
This research was supported by grants from the New Zealand Health Research Council, the Neurological Foundation of New Zealand, National Institute of Health grant NS021184 and the University of Otago.
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