Long-term depression: not so depressing after all.

Long-lasting activity-dependent changes in the efficacy of synaptic transmission in the mammalian brain are considered to be of fundamental importance for the development of neural circuitry and for the storage of information. The most compelling and reliable model for such changes has been long-term potentiation (LTP) in the hippocampus, a long-lasting increase in synaptic strength normally induced by repetitive high-frequency activation of presynaptic afferents (1). With the advent of in vitro brain slice preparations and their inherent experimental advantages, an enormous effort by a cadre of researchers over the last decade has resulted in detailed (and sometimes controversial) hypotheses concerning the cellular and biochemical mechanisms responsible for LTP (2). A nagging problem concerning the utility of LTP as either an important developmental or memory-storage mechanism has been the inability to define and characterize experimental paradigms that reliably decrease synaptic strength. Although a long-term depression (LTD) of synaptic transmission is not absolutely necessary to constrain LTP, which does exhibit a finite decay, neural networks with the ability to modify synaptic strength in both directions have enormous flexibility and power. Recently, over the last year or so, significant progress has been made in the experimental analysis of LTD in the mammalian brain. It appears that LTD, like LTP, is not a single uniform phenomenon but rather must be considered a generic term that is used to describe any long-lasting decrease in synaptic strength. Nevertheless, some common themes concerning the mechanisms of LTD in different brain regions are beginning to emerge. Because the induction of most forms of LTP requires synaptic activation of N-methyl-D-aspartate (NMDA) receptors (one of the several subtypes of receptor activated by the excitatory neurotransmitter glutamate) during strong postsynaptic depolarization (2), LTP is considered a biological correlate of the Hebb postulate (3), which in principle predicts an increase in synaptic efficacy when presynaptic and postsynaptic activity are strongly correlated. The requirement for NMDA receptor activation also explains the important property of LTP referred to as input or synapse specificity; only those synapses activated by the LTP-inducing stimulus exhibit LTP. In contrast, early work in the hippocampus both in vivo and in vitro demonstrated that when LTP is induced in one population of synapses, a modest depression may occur at some of the inactive synapses on the same population of postsynaptic cells (4-6). In a classic paper that anticipated this finding (and that was published in this journal almost exactly 20 years ago) Stent (7) proposed that such "heterosynaptic" decreases in synaptic efficacy could be explained by an extension of the Hebb rule; synaptic strength will decrease at inputs that are quiescent or weakly active when the postsynaptic cell is very active. While theoreticians over the ensuing two decades convincingly demonstrated the importance of algorithms that could decrease synaptic strength (8-10), experimental work on LTD lagged far behind, especially when compared to the enormous effort aimed at understanding the mechanisms of LTP. Thus, several years ago, considerable excitement was generated by the report that LTD could be generated in the CAl region of hippocampal slices when synaptic inputs were stimulated either outof-phase with short bursts of stimuli given to an independent conditioning input or during direct hyperpolarization of the postsynaptic cell (11). This LTD was of particular interest because it was "homosynaptic," occurring only at those synapses activated by the stimulation, and because its induction obeyed the converse of the Hebb rule (i.e., synapses were weakened when their activity did not correlate with significant postsynaptic activity). Unfortunately, disappointment soon followed as many laboratories had difficulty replicating this phenomenon (12). However, optimism and enthusiasm are on the rise recently as it appears that there are indeed forms of LTD that are amenable to rigorous experimental attack (not only in the hippocampus but also in the cerebellum and cerebral cortex). A common theme that emerges from the results to date is that, like LTP, changes in postsynaptic Ca2+ levels are required for the generation of LTD, although the specific characteristics of this Ca2+ signal may differ. In the CAl region of the hippocampus, prolonged, low-frequency (1 Hz) afferent stimulation produces a saturable and stable homosynaptic (i.e., synapse specific) LTD (13, 14). Surprisingly, the induction of this form of LTD is quite similar to LTP in that it requires activation of NMDA receptors (13, 14) and is blocked by strong hyperpolarization or buffering postsynaptic Ca2+ (14). Homosynaptic LTD has much in common with previous reports of "depotentiation" following LTP (15, 16); in fact, recent evidence suggests that homosynaptic LTD and LTP are reversal modifications of some common expression mechanism (17). However, a significant difference between homosynaptic LTD and LTP may be their developmental profile, since LTD appears to be more robust in slices prepared from young animals (14, 17). The mechanisms of heterosynaptic LTD have also been examined recently in the CAl region of hippocampal slices. This form of LTD is often quite small in magnitude (18) or requires unusual induction conditions (i.e., complete blockade of synaptic transmission during induction) (19). Nonetheless, changes in postsynaptic Ca2+ again appear to be required, although in this case Ca2+ is supplied via activation of voltage-dependent Ca2+ channels (18, 19). In the cerebellum, an absolute requirement for the LTD of the parallel fiber (PF)-Purkinje cell (PC) synapse induced by simultaneous climbing-fiber (CF) activation is a rise in postsynaptic Ca2+. The evidence includes the following observations: (i) CF activation can be replaced by direct depolarization of PCs (20, 21), (ii) both manipulations result in large increases in dendritic Ca2+ level (21), and (iii) LTD is blocked by loading PCs with Ca2+ chelators (21, 22) or by removing external Ca2+ (20). Activation of a metabotropic glutamate receptor (20, 23) possibly coupled to activation of protein kinase C (24) also appears to be necessary for cerebellar LTD. Questions that remain about this form of LTD include whether activation of the synaptic non-NMDA receptor is necessary for