This Week in The Journal

Regulation of Synapse Maturation by DSCAM

Peng Chen, Ziyang Liu, Qian Zhang, Dong Lin, Lu Song, et al.

(see pages 532–551)

Cell adhesion molecules (CAMs) have many roles in nervous system development. They guide neuron migration and axon growth, mediate target recognition, and initiate synapse assembly. After the developmental period, CAMs remain essential for stabilizing synapses and neurites. It is unsurprising, therefore, that copy number variations and mutations in CAM genes have been linked to several neurodevelopmental conditions. For example, mutations in presynaptic neurexins and postsynaptic neuroligins—CAMs whose interaction triggers synapse formation and maintains synapse stability—have been linked to autism. Mutations in Down syndrome CAM (DSCAM), one of the genes duplicated in people with Down syndrome, have also been linked to autism. Chen, Liu, et al. now establish a link between these molecules, showing that DSCAM regulates binding between neurexins and neuroligins.

DSCAM expression in mouse brain increased along with synaptogenesis, peaking around postnatal day 12, after which expression declined. Consistent with a role in synapse formation, DSCAM was expressed in puncta in dendritic shafts and immature-looking spines, but less so in mature-looking spines. Furthermore, deleting DSCAM in neural progenitor cells led to increases in the length of dendrites, the density of mature spines, and the width of spine heads in postnatal cortex. The number of functional synapses also increased, as indicated by an increase in the frequency of miniature EPSCs. Time-lapse recording in cortical cultures revealed that increased spine density resulted from increased stability and decreased elimination, rather than increased spine formation. Most intriguingly, binding assays revealed that DSCAM and neuroligin1 interact via their extracellular domains and that this interaction inhibits binding between neuroligin1 and neurexin1β. Moreover, addition of the DSCAM extracellular domain to the culture medium of cortical neurons rescued spine density after DSCAM knockdown.

These results suggest that DSCAM restrains synapse stabilization by binding to neuroligin1, thus interfering with neurexin1β binding. Consequently, loss of DSCAM leads to excessive spine stabilization and increased excitatory input to neurons. This may have some benefits: DSCAM-deficient mice performed better than controls on a spatial memory task. However, it likely also limits circuit flexibility, and it led to other behavioral changes, such as increasing circling and self-grooming, reducing preference for an unfamiliar over a familiar mouse, and increasing avoidance of open areas.

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Knocking down DSCAM increases the density of mature-looking spines in cortical neurons. See Chen, Liu, et al. for details.

Effects of Breathing and Heart Rate on Tactile Perception

Martin Grund, Esra Al, Marc Pabst, Alice Dabbagh, Tilman Stephani, et al.

(see pages 643–656)

If you are waiting for an improbable occurrence, a friend might advise you not to hold your breath. But why would you hold your breath in anticipation? One possible reason is that respiration modulates brain activity and thus can affect the ability to detect faint stimuli. Respiration also affects heart rate (heart rate increases during expiration and decreases during inspiration), and heartbeats can affect sensory perception. Indeed, weak stimulation of a finger is most likely to be detected if it is delivered just before the heart beats. Grund et al. elucidate how the cardiac and respiratory cycles interact to influence not only somatosensory perception, but also people's confidence about perceptions.

The researchers applied near-threshold electrical pulses to participants' fingers, so stimulation was detected ∼50% of the time. Consistent with previous work, detection was most likely when the stimulus was delivered in the last quarter of the cardiac cycle (during ventricular diastole). This relationship only held for trials on which subjects were confident of their decision, however. In contrast, subjects often expressed confidence that no stimulation had occurred if stimulation was delivered in the second quarter of the cardiac cycle—about the time the pulse wave reached the finger.

Detection of near-threshold stimuli was also associated with slowing of the heart. This was related to the fact that stimuli were most likely to be detected if they occurred during the first quarter of the respiratory cycle; that is, during expiration. Notably, participants appeared to adjust their respiratory cycle so that stimuli (which occurred at a fixed interval after a cue) would be delivered when tactile perception was greatest.

These results suggest that one reason tactile perception varies across the cardiac cycle is that the arrival of the pulse wave at the finger masks external stimuli. The study also shows that stimulus detection is greatest during exhalation, in part because the cardiac cycle is slower. Most importantly, the study demonstrates that by timing their breathing appropriately, people may increase their ability to detect faint tactile stimuli.