Role of DSCAM in Cortical Expansion
Tao Yang, Macy W. Veling, Xiao-Feng Zhao, Nicholas P. Prin, Limei Zhu, et al.
(see pages 5510–5521)
Down syndrome results from trisomy of chromosome 21. One of the genes present on this chromosome, Down syndrome cell adhesion molecule (DSCAM), has roles in dendritic arborization, dendritic spine formation, and the initiation of migration in the developing brain. Although DSCAM can engage in homophilic binding, at least some of its effects stem from its ability to disrupt adhesion mediated by other molecules, particularly N-cadherins. Yang et al. suggest that this property is required for the normal expansion of upper cortical layers.
During cortical development, neurons generated in the ventricular and subventricular zones migrate outward toward the surface of the brain. The earliest born neurons form the deepest cortical layers, and later-born neurons migrate through these layers to form the upper layers. Yang et al. found that cortical development in DSCAM-null mice proceeded normally through embryonic day 17.5, just before upper-layer neurons began to be generated. By postnatal day 5, however, the upper cortex (layers 2–4) was ∼25% thinner in DSCAM-null mice than in controls. This thinning did not result from a loss of upper-layer neurons or from the failure of these neurons to migrate through lower cortical layers. Indeed, DSCAM-deficient upper-layer neurons were generated and migrated normally until reaching the upper boundary of the developing cortex. Instead of pushing that boundary outward, however, they stopped migrating, resulting in an ∼25% greater-than-normal packing density in upper layers. Time-lapse imaging confirmed that DSCAM-deficient neurons stopped migrating as they reached the marginal zone above the cortical plate. Moreover, examination of neurons migrating along the same radial glial fiber revealed that whereas ∼67% of later-migrating neurons in control cortex overtook earlier migrating neurons, only ∼11% of DSCAM-deficient neurons did so. To investigate a potential interaction between DSCAM and N-cadherin in cortical expansion, the authors examined the ability of N-cadherin-expressing HEK cells to bind to upper layers in cortical slices. Such binding was disrupted by pretreating cells with N-cadherin antibodies or by coexpressing DSCAM in the cells.
These results suggest that DSCAM prevents excessive adhesion between upper-layer cortical neurons, thus promoting radial expansion of the cortex. Future work should determine whether overexpression of DSCAM leads to insufficient N-cadherin-mediated binding and whether this contributes to Down syndrome-related phenotypes.
Time-lapse imaging of GFP-expressing pyramidal neurons (green) reveals that in DSCAM-deficient mice, upper-layer pyramidal neurons (red) stop migrating when they reach the upper boundary of the cortical plate, leading to thinner and denser superficial layers. See Yang et al. for details.
Effects of M2 Muscarinic Receptors on Habenula Physiology
Clara I.C. Wolfe, Eun-Kyung Hwang, Elfrieda C. Ijomor, Agustin Zapata, Alexander F. Hoffman, et al.
(see pages 5552–5563)
The lateral habenula (LHb) is a diencephalic structure best known for signaling negative events. It integrates excitatory and inhibitory input from multiple brain areas, including the basal ganglia, hypothalamus, extended amygdala, and prefrontal cortex, and it indirectly inhibits midbrain dopamine neurons via glutamatergic projections to the rostromedial tegmental nucleus. Consequently, whereas LHb neurons spike more when outcomes are worse than expected and less when outcomes are better than expected, midbrain dopamine neurons show the opposite pattern. Furthermore, whereas activation of dopamine neurons typically reinforces recent behavior, activation of the LHb may lead to behavioral changes. Consistent with this, when LHb is inhibited by injecting GABA agonists, rats continue seeking cocaine in the presence of a cue previously established as an indicator that no cocaine is present. Interestingly, infusing an inhibitor of muscarinic acetylcholine receptors (mAChRs) has a similar effect, suggesting that acetylcholine normally regulates LHb activity. Wolfe et al. now identify the type of mAChR responsible for this effect and examine how these receptors influence synaptic transmission in the LHb.
Consistent with previous work, muscarinic agonists evoked inward (excitatory) currents in most LHb neurons recorded in brain slices. The agonist also decreased the frequency and amplitude of spontaneous EPSCs, the frequency of spontaneous IPSCs, and the amplitude of IPSCs evoked by local electrical stimulation or optical stimulation of channelrhodopsin-expressing projections from the ventral tegmental area. Importantly, however, the inhibition of EPSCs was greater than the inhibition of IPSCs, so the ratio of excitatory to inhibitory currents was reduced in the presence of a muscarinic agonist. Notably, the effects of muscarinic agonists were blocked by an antagonist of M2 mAChRs, but not an antagonist of M1 mAChRs, and infusion of the M2 mAChR antagonist into the LHb increased cocaine seeking in the presence of a cue signaling that no cocaine was available.
These data suggest that activation of M2 mAChRs reduces both inhibitory and excitatory input to LHb neurons. The effect on excitatory input is greater, however, resulting in a relative increase in the influence of inhibitory input. Consequently, when a rat is unsuccessful in obtaining a reward such as cocaine, the LHb error signal may be too small to inhibit reward seeking.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
