Psd95 Accumulation

PSD-95 was identified in the early 1990s by cDNA cloning of PSD proteins14.

Since then, it has been regarded as the prototypical PSD scaffolding protein. A

protein interaction domain, of which PSD-95 contains three, is seen in hundreds of such scaffolding proteins and was named after PSD-95 and its Drosophila homolog: the PDZ domain (PSD-95, Discs large, and ZO-1). In addition to the

PDZ domains, PSD-95 presents an inactive guanylate kinase domain, making it a member of the large family of membrane-associated guanylate kinases

(MAGUKs)15. PSD-95 has been regarded as the fail-safe marker of the mature glutamatergic synapse and by virtue of its direct and indirect interactions with NMDA and AMPA receptors, PSD-95 has been considered a key player in the development of the PSD.

Before extensive time-lapse studies were carried out, PSD-95 had been recognized as playing an important role in synaptic strength at mature synapses16.

In fact, it was shown that for PSD-95 to function in synaptic plasticity, this essentially cytosolic molecule needs to become membrane bound by palmitoylation17. This interesting mechanism may also be required in its recruitment to new synapses (discussed below). The huge importance of PSD-95

allowing mature synapses to grow in response to activity18, suggested a function in early synapse formation and maturation. With this in mind, the dynamics of PSD-95 before, after, and during synapse formation have been studied extensively.

As mentioned above, PSD-95 has been clearly seen to localize in clusters within the dendrites of hippocampal and cortical neurons prior to synapse formation6. This distribution was confirmed by imaging of GFP-tagged forms of PSD-959,18-20. These clusters have been shown to be largely immobile9,18-21, suggesting that they do not represent transport modules of PSD-95. EM studies have shown nonsynaptic membrane specializations or "free PSDs"22,23, however, the nature of these structures remains obscure. Since PSD-95 has been shown to accumulate gradually at nascent synapses from a cytoplasmic pool18-20, one may guess that these clusters act as protein reservoirs within the dendrites of neurons.

In contrast, a number of studies have shown some movement of PSD-95 clusters, albeit very slow (up to 1 |im/min)24. The dynamics for PSD-95 clusters include splitting of clusters24,25, lateral movement in shafts24, movement into and out of established spines, and movement within dendritic filopodia24,25. Spines represent the final maturation step of glutamatergic synapses. These stable, mushroom-shaped protrusions from the dendritic shaft are thought to act as compartments for the restriction of local second messenger systems to individual postsynaptic densities26. In contrast, dendritic filopodia are highly dynamic protrusions, which are thought to be involved in initiating synaptogenic contact and comprise morphological precursors of synaptic spines27.

Since these studies did not address the colocalization of presynaptic terminals with the individual moving clusters of PSD-9524,25, it is unclear whether they can be regarded as transport modules. It is possible that these clusters constitute assembled postsynaptic densities opposing presynaptic terminals, which, with a certain low probability, can move out of and into spines. Another possibility is that an assembled, free PSD can move during assembly and disassembly of the synapse. It remains to be determined what these PSD-95 clusters exactly represent and which other proteins are associated with them.

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