Abstract
The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD) techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h.
Highlights
Long-term potentiation (LTP) is a persistent increase in the efficiency of synaptic transmission following high-frequency or patterned stimulation of input pathways
Late-phase LTP (LTP2 and LTP3) in vivo requires de novo protein synthesis [11,12,13] and we have shown that 48 h post-induction, LTP is associated with increased overall expression of GluA1 and GluA2 protein in the dentate gyrus [14], but no change in their expression in synaptoneurosome surface membrane or postsynaptic densities (PSDs) fractions
Tissue from four subregions of the dentate gyrus was microdissected from 10 alternate sections, namely the middle molecular layer (MML) and granule cell layer (GCL) (Fig. 1A), and the outer and inner molecular layer (OML and IML, respectively) from the corresponding alternate sections (Fig. 1B), giving 20 sections in all
Summary
Long-term potentiation (LTP) is a persistent increase in the efficiency of synaptic transmission following high-frequency or patterned stimulation of input pathways. The mechanisms that mediate the induction and early expression of LTP are increasingly well-described, including the activation, modification and recruitment of postsynaptic ionotropic glutamate receptors As it is the long-lasting nature of LTP that gives its relevance to longterm information storage, it is important to understand the late expression and maintenance of LTP; yet the molecular events that underlie persistent LTP are poorly understood. Increased numbers of immunogold-labelled AMPARs are present at perforant path synapses 75 min following induction of LTP in the dentate gyrus of anaesthetized rats [9], while increased levels of the GluA1 and GluA2 AMPAR subunits occur 20 min after the induction of LTP in the dentate gyrus of awake animals [10] In these latter experiments, we observed protein synthesis-independent increases in GluA1 and GluA2 expression in synapse-enriched biochemical fractions (synaptoneurosomes) and surface membranes, while only GluA1 was elevated in isolated postsynaptic densities (PSDs). These data are strongly suggestive of an important role for homomeric GluA1 receptors in the early period following LTP induction
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