It is well established that synaptic strengthening involves the recruitment of AMPARs to the postsynaptic membrane. However, the subunit composition of the receptors has not been investigated closely, so the studies discussed here allow for refinement of this basic model, as they all show that synaptic strengthening involves the incorporation of Ca2+-permeable GluR2-lacking AMPARs to the postsynaptic membrane of active or recently-potentiated synapses.
The studies further demonstrate that synaptic plasticity involves switching of AMPAR subtypes. Bellone and Luscher show that cocaine-triggered insertion of GluR2-lacking AMPARs is preceded by, and is dependent upon, the removal of heteromeric AMPARs. Plant et al demonstrate that hippocampal LTP, the most extensively studied form of plasticity, involves the replacement of newly-incorporated GluR2-lacking AMPARs by hetermeric receptors, and that this occurs within 20 minutes of LP induction.
Activity-dependent insertion of GluR2-lacking AMPARs into the postsynaptic membrane has now been demonstrated in dopaminergic midbrain neurons, neocortical pyramidal cells, and cultured hippocampal cells and slices. It has also been observed in cultured cerebellar stellate cells (Liu and Cull-Candy, 2000).The process occurs in vitro and in vivo, in a number of cell types in different regions of the brain, and may, therefore, be a general requirement for synaptic plasticity.
Harm et al and Clem and Barth observed that synaptic activity regulates GluR1 levels in a synapse-specific manner. More recently, Ehlers et al (2007) used semiconductor quantum dots conjugated.with anti-GluR1 antibodies, in combination with fluorescence microscopy, to monitor the surface mobility of AMPARs. They found that GluR1 movement was severly restricted at active synapses, but not at adjacent silenced synapses. Thus, it seems that synaptic activity can initiate synapse-specific signaling cascades which regulate the distribution of GluR1 AMPARs on a sub-micrometer scale, and that AMPARs can shuttle between neighbouring active and inactive synapses.
Although these studies further elucidate the postsynaptic modifications that underly synaptic strengthening, many issues are, as yet, unresolved. Plant et al found that the GluR2-lacking AMPARs inserted into the membrane of CA1 neurons in hippocampal LTP were replaced by heteromeric AMPARs approximately 20 minutes later. However, Clem and Barth observed inward rectification 24 hours after whisker stimulation, and Bellone and LÃ¼scher observed significant rectification 48 hours after administration of cocaine. It appears, then, that the timescale of synaptic retention of Ca2+-permeable AMPARs depends upon the type of plasticity in question.
The activity-dependent insertion of GluR1 AMPARs is known to require phosphorylation of serine 818 on the GluR1 subunit (Boehm et al, 2006), but other components of the signalling pathways which mediate the rapid membrane trafficking of AMPARs remain to be identified. Presumably, at least some of these proteins will contain the PDZ domain, which is known to mediate protein-protein interactions and to bind to the carboxy terminus of all AMPAR subunits, including GluR1.
As well as increasing the amplitude of EPSCs, newly-inserted Ca2+-permeable AMPARs are likely to have other functions. The additional source of Ca2+ may, for example, be required for the subsequent recruitment to the postsynaptic membrane of heteromeric AMPARs, or for initiating changes in dentritic spine morphology. In the case of hippocampal LTP, Plant et al further suggest that Ca2+ influx through GluR2-lacking AMPARs induces the protein synthesis and changes in gene expression on which LTP is known to be dependent. Thus, the transient incorporation into the postsynaptic membrane of GluR2-lacking AMPARs may be necessary for consolidating the early phase of LTP, such that synaptic strengthening can continue for long periods of time. Future work may shed light on these outstanding issues.
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