The ups and downs of synaptic plasticity: influences on this particular ‘market’

In the current economic climate it is all too apparent that what goes up can also go down; the same is true for the strength of glutamatergic excitatory postsynaptic potentials/currents (EPSPs/EPSCs). What is less apparent is what underlies changes when they occur. There can be no doubt that the exquisite detail of synaptic connectivity in the mammalian brain is suggestive of its power to store and process information. Such a static image of the nervous system – complex though it may be in isolation – acquires a deeper significance when we witness its ability to change: synapses are plastic and synaptic activity controls plasticity. This dynamic re-wiring of synaptic connections is now the pre-eminent physiological model for learning and memory. Indeed, dissecting the rules that govern synaptic plasticity has kept investigators busy since the seminal paper by Tim Bliss and Terje Lømo published in The Journal of Physiology (Bliss & Lømo, 1973) in which they showed that bursts of high frequency, ‘tetanic’, stimulation of the perforant path of the hippocampus led to a persistent increase in the strength of synaptic connections, a phenomenon known as long-term potentiation (LTP). Since then, a host of other ‘learning rules’ for excitatory synapses has emerged. These include long-term depression (LTD), a weakening of synaptic strength which results from low frequency stimulation, and ‘theta-burst LTP’, arising from trains of stimulation that mimic the endogenous theta band activity in the hippocampus. More recently, evidence has emerged that the precise timing of repeated pre- and postsynaptic action potentials can strengthen or weaken EPSPs/EPSCs, so-called spike timing-dependent plasticity (STDP).

What subcellular mechanisms underlie these learning rules? In the hippocampus, especially at CA1–Schaeffer collateral synapses, we already know that many forms of plasticity, including LTP, LTD and STDP, depend on the activation of N-methyl-d-aspartate receptors (NMDARs) and are expressed as changes in the amplitude of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated EPSPs/EPSCs. This cause-and-effect scenario requires signalling molecules resident at the synapse to couple NMDAR activation to mechanisms that regulate AMPAR expression. Systematic attempts to identify the proteins involved in this signalling complex have resulted in a catalogue of hundreds of molecules (Collins et al. 2006). Among these are several members of the membrane-associated guanylate kinase (MAGUK) family, including PSD-93 and PSD-95, two proteins that interact specifically with NMDARs and which are the focus of a paper in this issue of The Journal of Physiology by Carlisle et al. (2008).

MAGUKs represent a family of signalling molecules that are evolutionarily conserved across species as diverse as drosophila, mouse and human (Funke et al. 2005). All multicellular organisms need such molecules to couple intracellular communication to differentiation and coordinated growth. Nowhere is such a precise interplay between ultrastructural changes and signalling more crucial than at synapses, where both PSD-93/95 are found. In this issue of The Journal of Physiology, Carlisle et al. (2008) have uncovered distinct roles for each of these proteins in LTP and LTD by examining the plasticity phenotype in PSD-93/95 mutant mice. The main ‘take home’ messages from this study can be summarized as follows. When compared to wild-type littermates, mice expressing a mutant form of PSD-95 (Migaud et al. 1998) display (1) impaired basal AMPAR-mediated synaptic transmission, (2) enhanced tetanus-, theta-burst-, and STDP-induced LTP, and (3) no LTD. In contrast mice lacking PSD-93 display (1) normal levels of basal AMPAR-mediated synaptic transmission, (2) normal tetanus-induced but impaired theta-burst- and STDP-induced LTP, and (3) normal levels NMDAR-dependent LTD. As with many studies of synaptic plasticity, details matter, and this summary needs expanding upon. First, two earlier studies using the same form of PSD-95 mutant mice concluded that basal AMPAR-mediated transmission is normal (Migaud et al. 1998; Elias et al. 2006). While the discrepancy between Elias et al. (2006) and the current study may be accounted for by the age of the mice used, a reassessment of the other study (Migaud et al. 1998) conducted by Carlisle et al. (2008) confirms reduced AMPAR-mediated basal synaptic transmission. Perhaps this reduced basal AMPAR expression in PSD-95 mutants engenders a greater capacity for increasing synaptic strength. Certainly it appears from this and earlier studies (Migaud et al. 1998) that potentiation is not only stronger, but can also result from stimulation protocols that do not normally give rise to changes in synaptic strength, such as single spike-pairing STDP. Does PSD-95 therefore participate in a signalling pathway that simultaneously limits the strength of potentiation and its sensitivity to the temporal order of pre- and postsynaptic events? If so, it is somewhat surprising that acute slices show impaired basal transmission: one might expect that ‘experiences’ of PSD-95 mutants (during their lives) may have triggered inappropriate synaptic strengthening and therefore an increase in basal synaptic transmission. Thus while LTP in vitro and mechanisms of experience-dependent plasticity in vivo share common features (Whitlock et al. 2006) it remains difficult to interpret results such as this in both contexts. In this respect it would be useful to know the temporal characteristics of late-phase (protein synthesis-dependent) LTP in hippocampal slices obtained from PSD-95 mutants.

PSD-93 mutants show more subtle changes in synaptic transmission/plasticity compared to PSD-95 mutants. Basal synaptic transmission, tetanus-induced LTP and low frequency-induced LTD are indistinguishable from wild-type and it is only in theta burst-induced LTP and STDP that deficits are apparent. This might indicate that the levels of intracellular calcium triggered by the various protocols are crucial for understanding the role of PSD-93 in particular. In conclusion, the study by Carlisle et al. (2008) demonstrates that PSD-93 and PSD-95 have opposing effects on plasticity in the CA1 region of the hippocampus; however a challenge that emerges is to understand how expression levels of MAGUKs are regulated if proteins such as these are part of the currency used to determine the ‘synaptic economy’.