Activity and synaptic receptor targeting: the long view.

In each of these synapses, activity of a particular receptor type regulates its own subcellular distribution over a time course of days. Considering that these systems have evolved completely different modes and means of activity-dependent regulation of synaptic receptor targeting, it is particularly satisfying that each of these phenomena can not only be rationalized post hoc but were actually predicted on theoretical grounds. The general applicability of these models of receptor targeting underlying denervation supersensitivity, activity-dependent synapse stabilization, synaptic scaling and metaplasticity, and competitive synapse elimination needs to be assessed in other synapse types. For example, although this review focuses on vertebrate synapses, it is noteworthy that Drosophila glutamatergic neuromuscular synapses are like vertebrate glycinergic synapses in requiring activity for stabilization of postsynaptic receptors, but they also show homeostatic regulation at the level of bouton number and transmitter release (reviewed by Broadie 1998xBroadie, K. Curr. Opin. Neurobiol. 1998; 8: 128–138Crossref | PubMed | Scopus (19)See all ReferencesBroadie 1998).One of the outstanding questions regarding central synapse formation is how the appropriate pre- and postsynaptic components become matched and aligned for each chemical synapse type (Craig et al. 1994xCraig, A.M, Blackstone, C.D, Huganir, R.L, and Banker, G. Proc. Natl. Acad. Sci. USA. 1994; 91: 12373–12377Crossref | PubMed | Scopus (219)See all ReferencesCraig et al. 1994). Theoretically, stabilization via activation of synaptic receptors by their appropriate transmitters would be a satisfying means of matching presynaptic and postsynaptic components. According to this hypothesis, synaptic release of GABA could stabilize apposing GABA receptors but not glutamate receptors, and synaptic release of glutamate onto a neighboring site on the same dendrite could stablilize apposing glutamate but not GABA receptors. However, the prediction of this model, that activity is required for stabilization of synaptic receptors, was found only for GlyRs, but not for GABAA receptors or AMPA- or NMDA-type glutamate receptors, as reviewed above. Thus, receptor activation does not appear to be a general means for generating selectivity in receptor clustering among postsynaptic sites, and we are forced to contemplate more complex molecular models.The molecular mechanisms underlying the activity-dependent control of receptor localization are largely understood only for global activity manipulations at the neuromuscular junction (Duclert and Changeux 1995xDuclert, A and Changeux, J.-P. Physiol. Rev. 1995; 75: 339–368PubMedSee all ReferencesDuclert and Changeux 1995). An immediate goal for the other model systems is to uncover the mechanistic cascades leading from depolarization, local Ca2+ influx, or changes in receptor conformation to changes in receptor targeting. Synaptic receptor density is determined by a large number of steps, collectively referred to here as receptor targeting. These steps include rates of receptor synthesis and degradation, sorting into transport vesicles, trafficking of these vesicles, insertion into or removal from the plasma membrane by exocytosis and endocytosis, and diffusion, trapping, or anchoring within the membrane (for a general discussion, see Craig and Banker 1994xCraig, A.M and Banker, G. Annu. Rev. Neurosci. 1994; 17: 267–310Crossref | PubMedSee all ReferencesCraig and Banker 1994). It is likely that many of these steps are regulated, as is true for targeting of other receptors in polarized epithelial cells (Mostov et al. 1995xMostov, K.E, Altschuler, Y, Chapin, S.J, Enrich, C, Low, S.-H, Luton, F, Richman-Eisenstat, J, Singer, K.L, and Weimbs, T. Cold Spring Harbor Symp. Quant. Biol. 1995; 60: 775–781Crossref | PubMedSee all ReferencesMostov et al. 1995).One of the most interesting sequelae of the recent cell culture studies of activity-dependent modulation of glycinergic and glutamatergic synapses is the number of important questions raised. Can these phenomena be observed in vivo, and are they developmentally restricted? In contrast to the large pharmacological manipulations, can more subtle long-term physiological changes in activity levels also modulate synaptic receptor targeting, and can we quantitatively predict outcomes? Does activity control receptor targeting at the level of an individual synapse? These questions offer a challenge for creative use of recent advances in imaging techniques.