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pyramidal neuron in the local microcircuit.In fact, in most cases neurons ‘touch’ eachother several times, and the likelihood thattwo neurons touch is unrelated to whetherthey are functionally connected (as revealedby simultaneous recordings). However, neu-rons that were functionally connected weremore likely to be connected by putativesynapses, as would be expected.

The authors interpret the apparently ran-dom formation of physical contact betweenneurons as a kind of tabula rasa — a flexiblepattern of potential circuitry on which can beimposed any required functional microcir-cuit. The large number of contacts betweenneighbouring pyramidal neurons could alsobe important for cortical plasticity, as it mightallow the formation of new synapses withoutaxons or dendrites having to change theirmorphology.

Rachel Jones

References and linksORIGINAL RESEARCH PAPER Kalisman, N. et al. Theneocortical microcircuit as a tabula rasa. Proc. Natl Acad. Sci.USA 102, 880–885 (2005)

It is already known that the postsynapticadhesion molecule neuroligin 1, incomplex with its axonal receptor,β-neurexin, is involved in presynapticterminal formation. Now, new researchpublished in Science shows that the samecomplex is also involved in postsynapticdifferentiation, and that neuroligins havean important role in maintaining thefunctional balance of excitatory andinhibitory synapses.

Chih and co-workers first showed thatneuroligin overexpression in cultured rathippocampal cells increased both theformation of dendritic spines and therecruitment of postsynaptic molecules,including NMDA (N-methyl-D-aspartate)receptors.

They then used two neuroligin 1 mutantsto investigate the involvement of neuroliginin postsynaptic density moleculerecruitment and scaffolding assembly. Adominant-negative mutant with a disrupted

β-neurexin-binding site inducedpostsynaptic clustering of the scaffoldingmolecule postsynaptic density protein 95(PSD-95), but the clusters were misalignedwith the presynaptic terminals.

In the second mutant, the loss of neuro-ligin’s PDZ-binding motif resulted in apredictable absence of PSD-95 clustering,but no severe effect on NMDA receptorclustering was seen, indicating that NMDAreceptor recruitment is largely independentof PSD-95 clustering. Therefore, the PDZ-binding motif is required for PSD-95clustering, whereas the β-neurexin-bindingsite is needed for the clusters to align withpresynaptic terminals.

In rodents, there are three neuroliginisoforms, and knockdown of each singleisoform resulted in a significant reductionin the number of excitatory and inhibitoryterminals. This indicates that there is somefunctional overlap between the neuroliginisoforms.

Chih et al. also found that excitatory andinhibitory neurotransmission were notequally perturbed by neuroligindownregulation — inhibitoryneurotransmission was affected far more thanexcitatory neurotransmission, which resultedin an imbalance of cellular activity. So far, thereasons for this preferential effect oninhibitory transmission are unknown, but theauthors suggest that excitatory synapses mightbe better able to produce a compensatoryupregulation in activity. Moreover, at normalneuroligin levels, a significant proportion ofexcitatory synapses are silent, and loss of thesesynapses will not alter cellular excitation.

Sarah Archibald

References and linksORIGINAL REFERENCE PAPER Chih, B. et al.Control of excitatory and inhibitory synapse formation byneuroligins. Science 27 January 2005(doi:10.1126/science.1107470)FURTHER READING Dean, C. et al. Neurexin mediates the assembly ofpresynaptic terminals. Nature Neurosci. 6, 708–716 (2003)

Neuroligin: the synaptic multitasker

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

Reach out and touch

C E R E B R A L C O RT E X

R E S E A R C H H I G H L I G H T S

In the densely packed neocortex, neuronsform synaptic connections with only aselected subset of their neighbours. Kalismanet al. investigated how neurons control thisselective connectivity, and found that theaxons of pyramidal neurons are not selectivein terms of physical contact with neighbour-ing dendrites; rather, they touch the dendritesof all neighbouring neurons, but make synap-tic contacts with only a few of them.

Although it is clear that pyramidal cellaxons must select their targets at some level, ithas been hard to discover whether they pro-ject to specific dendrites within the localmicrocircuit, or instead project ‘randomly’and form synapses at only a subset of contactpoints. To distinguish between these possibili-ties, Kalisman and colleagues used simultane-ous multineuron recording combined withconfocal microscopy to compare the func-tional connections between cortical neuronswith their structural properties.

The key finding of the confocal micro-scopy was that a pyramidal neuron makesphysical contact with every other neighbouring

A confocal image of two layer 5 pyramidal cells on a backgroundof reconstructed neurons, illustrating the fraction of choices fortarget cells. The upper insert shows an en passant axon‘touching’ a dendrite without forming a bouton and the lowerinsert shows an en passant axon touching and forming a boutonat the touch site. The latter pair of neurons were synapticallyconnected, whereas the former were not. Image courtesy of H. Markram, Brain Mind Institute, Lausanne, Switzerland.