166 | MARCH 2004 | VOLUME 5 www.nature.com/reviews/neuro

H I G H L I G H T S

The protein postsynaptic density 95,or PSD95, has been implicated in thecontrol of receptor trafficking duringsynaptic plasticity. In The Journal ofNeuroscience, Ehrlich and Malinowshow that PSD95 controls the incorp-oration of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors into thepostsynaptic membrane during plasticity both in vitro and in vivo.

It was previously shown thatexpression of PSD95 in hippocampalneurons in slice culture could mimiclong-term potentiation (LTP) byincreasing the recruitment of AMPAreceptors to the synapse, and that it also prevented the induction offurther LTP, indicating that the twophenomena probably shared a mech-anism. Now, Ehrlich and Malinowhave confirmed these findings andtaken them further by showing that PSD95 is also important for adifferent form of plasticity in vivo.

The authors investigated whetherPSD95 was involved in experience-driven plasticity in the barrel cortex of

young rats. At synapses between layerIV and layer II/III pyramidal neuronsin neonatal rats, sensory experiencefrom the whiskers causes an increasein AMPA receptors and consequentlystrengthens synaptic transmission.When the rats are deprived of sensoryexperience because their whiskers aretrimmed, this recruitment process isreduced. Ehrlich and Malinow foundthat expression of a PSD95–GFP(green fluorescent protein) constructin barrel cortex neurons in rats withtrimmed whiskers mimicked theAMPA receptor recruitment that is normally induced by sensory experience. Expression of PSD95 also occluded experience-dependentrecruitment of AMPA receptors tosynapses, and a dominant-negativeform of the protein blocked receptorrecruitment.

It is unclear how PSD95 drives therecruitment of AMPA receptors to thesynapse. The authors found thatmutations that prevented either itsassociation with the cell membrane or its binding to proteins with PDZ

LTP

Three-dimensional bioactive scaffolds holdgreat promise as substrates for generatingtissue from stem cells in vitro and forpromoting tissue regeneration in vivo.As reported in Science, Silva and colleagueshave developed a remarkable new nanofibrematrix that assembles spontaneously when it comes into contact with cells, and can beengineered to promote neuronaldifferentiation.

The authors constructed a molecule calledIKVAV-PA, which included the five-amino-acid motif IKVAV (isoleucine–lysine–valine–alanine–valine). This motif occurs in theextracellular matrix component laminin, andit has been shown to induce and direct thegrowth of neurites. The IKVAV-PA moleculescarried a net negative charge,and mutual repulsion prevented them from aggregating in solution at pH 7.4.However, when they were exposed to positiveions — for example, in living tissue — theyformed nanofibres and assembled into a gel-like matrix.

The authors added mouse neuralprogenitor cells to a solution of IKVAV-PA,prompting the formation of a matrix thatencapsulated the cells. The resulting scaffoldhad a high water content, which allowedefficient diffusion of nutrients. A highproportion of the progenitors differentiatedrapidly into neurons, as indicated by theexpression of specific marker genes andneurite outgrowth. By contrast, there waslittle evidence of astrocytic differentiation.A control molecule — EQS-PA — in whichthe laminin motif was replaced by the non-physiological sequence glutamic acid–glutamine–serine (EQS), was also capable ofself-assembly, but failed to induce neuronaldifferentiation.

Interestingly, the IKVAV-PA nanofibreswere also effective at promoting neuronaldifferentiation when they were presented toneural progenitors as a two-dimensionalsubstrate on a culture dish. The authorsproposed that the key to the success of thematrix is the high density of IKVAV epitope

that is presented to the cells, rather than thethree-dimensional conformation. A solubleIKVAV peptide added to an EQS-PA matrixwas far less efficient at stimulating neuronaldifferentiation than the IKVAV-PA scaffold,indicating that the epitope needs to beintegrated into the nanofibres to beappropriately presented.

Silva et al. found that the matrix could alsobe induced to assemble if it was injected intotissue, raising the tantalizing possibility thatit could be used to stimulate the regenerationof injured nerves in vivo. As the matrixassembles on contact with tissue, it could beinjected as a fluid at the injury site, whichwould be far less invasive than implanting apre-formed scaffold. Also, because theIKVAV-PA scaffold seems to suppressastrocytic differentiation, it is unlikely toexacerbate the injury by inducing glial scarformation. Further investigations shoulduncover the full potential of this intriguingmaterial.

Heather Wood

References and linksORIGINAL RESEARCH PAPER Silva, G. A. et al. Selectivedifferentiation of neural progenitor cells by high-epitopedensity nanofibers. Science 22 January 2004(doi:10.1126/science.1093783)FURTHER READING Silver, J. & Miller, J. H. Regenerationbeyond the glial scar. Nature Rev. Neurosci. 5, 146–156(2004)

Matrix revolutions in 3D

S T E M C E L L S

Putting receptors in their place

S Y N A P T I C P H Y S I O LO G Y

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