Homeostatic plasticity and NMDA receptor trafficking Isabel Pe ´ rez-Otan ˜o 1 and Michael D. Ehlers 2 1 Department of Neurosciences, CIMA, University of Navarra Medical School, Pamplona, 31008, Spain 2 Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA Learning, memory and brain development are associ- ated with long-lasting modifications of synapses that are guided by specific patterns of neuronal activity. Such modifications include classical Hebbian plasticities (such as long-term potentiation and long-term depression), which are rapid and synapse-specific, and others, such as synaptic scaling and metaplasticity, that work over longer timescales and are crucial for main- taining and orchestrating neuronal network function. The cellular mechanisms underlying Hebbian plasticity have been well studied and involve rapid changes in the trafficking of highly mobile AMPA receptors. An emerg- ing concept is that activity-dependent alterations in NMDA receptor trafficking contribute to homeostatic plasticity at central glutamatergic synapses. Introduction Most excitatory synapses exhibit a rich repertoire of plasticity modes that act over timescales ranging from milliseconds to weeks, and that have spatial dimensions ranging from individual synapses to all afferent synapses onto a neuron. Hebbian forms of plasticity alter the strength of specific synapses that exhibit coincident activity. Typically, correlated presynaptic and postsyn- aptic firing or high-frequency stimulation results in long- term potentiation (LTP) of synaptic strength, whereas low-frequency stimulation or uncorrelated firing yields long-term depression (LTD). Such fast, durable and selective modifications of synaptic strength are necessary for wiring the brain during development and for encoding information in response to experience. However, Hebbian forms of plasticity operate by positive feedback rules that, if left unchecked, tend to destabilize neuronal networks over time by driving neurons towards maximal and minimal action potential firing frequency ranges, which degrade propagating signals in the network and render neurons unable to encode subsequent plastic changes by Hebbian mechanisms [1]. Homeostatic forms of plasticity might provide the global negative feedback necessary to maintain synaptic strength and plasticity within a functional dynamic range, by scaling the strength of all synaptic inputs up or down while preserving their relative weights (synaptic scaling) or by altering the ability of synapses to undergo subsequent Hebbian modifications (metaplasticity) [2,3]. Alterations in synaptic strength can be encoded presynaptically as alterations in the machinery releasing the neurotransmitter glutamate, or postsynaptically by changing the number or function of receptors sensing the glutamate signal. A key advance has been the discovery that glutamate receptors are dynamically transported to and from the postsynaptic membrane. Such dynamic transport operates over a wide range of timescales and responds to diverse stimuli, matching the varied spectrum of plasticity modes. It is now widely accepted that the trafficking of AMPA-type glutamate receptors mediates rapid synaptic modification in the classic Hebbian forms of plasticity, LTP and LTD [4,5]. Several other cellular and molecular changes have been implicated in synaptic homeostasis but one common feature of many forms of homeostatic plasticity is an alteration in the number or complement of NMDA-type glutamate receptors [6–8]. Although the subject of extensive debate, the precise mechanisms triggering these changes and how they translate into persistent synaptic modifications to pre- serve the stability or plasticity of the network are still poorly understood. Because homeostatic plasticity often proceeds gradu- ally over hours or days [2,8–10], early studies focused on slow receptor turnover coupled to transcriptional changes as the main mechanism to effect NMDA receptor changes [11–13]. A series of new studies has revealed that NMDA receptors cycle rapidly into and out of synapses, and that regulated trafficking of NMDA receptors, working cumu- latively and over longer timescales, can effectively modify the number and composition of synaptic NMDA receptors (reviewed in Refs [14–16]). Here, we consider recently discovered ways (some predicted, others unexpected) in which activity-induced changes in NMDA receptor traf- ficking can drive non-Hebbian forms of synaptic plasticity. As a primary source of postsynaptic Ca 2C , NMDA receptors initiate rapid forms of synaptic plasticity, and the magnitude or duration of NMDA-receptor-mediated Ca 2C influx dictates the type and sign of plasticity induced [17,18]. A useful simplified framework has been that small amounts of NMDA-receptor-mediated Ca 2C influx pro- duce LTD whereas strong activation of NMDA receptors leads to LTP [18,19]. As will be discussed, chronic activity perturbations bidirectionally modify Ca 2C influx through NMDA receptors by adjusting the number of NMDA Corresponding authors: Pe ´rez-Otan ˜o, I. (otano@unav.es), Ehlers, M.D. (ehlers@neuro.duke.edu). Available online 22 March 2005 Review TRENDS in Neurosciences Vol.28 No.5 May 2005 www.sciencedirect.com 0166-2236/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2005.03.004