Cellular/Molecular
Cajal-Retzius Cells Excite Interneurons and Pyramidal Cells
Giulia Quattrocolo and Gianmaria Maccaferri
(see pages 13018–13032)
Cajal-Retzius cells occupy the marginal zones (future layer 1 and outer molecular layer) of the developing cerebral cortex and hippocampus. Cajal-Retzius cells are the first neurons to populate these structures, and they are the primary source of reelin, which guides migrating pyramidal neurons and is required for proper lamination. They also guide projections from the entorhinal cortex to the hippocampus. Cajal-Retzius cells receive synaptic inputs from GABAergic interneurons and neurogliaform cells, but their targets and the neurotransmitter they release have been unclear. Quattrocolo and Maccaferri addressed this question by expressing channelrhodopsin selectively in Cajal-Retzius cells. Optical stimulation of the cells in hippocampal slices from postnatal mice evoked AMPA- and NMDA-receptor-dependent currents both in interneurons and pyramidal neurons. By activating GABAergic interneurons, Cajal-Retzius cell stimulation also elicited delayed GABAergic currents in pyramidal cells. Because most Cajal-Retzius cells undergo apoptosis after the developmental period, the authors speculate that the cells' activity plays a role in the development of hippocampal circuits.
Channelrhodopsin-expressing Cajal-Retzius cells in the molecular layer of the dentate gyrus. For more information about these cells, see the article by Quattrocolo and Maccaferri.
Development/Plasticity/Repair
Deep Cortical Neurons Promote Generation of Upper Layers
Kenichi Toma, Takuma Kumamoto, and Carina Hanashima
(see pages 13259–13276)
Cortical projection neurons are generated from progenitors in the subventricular zone. The first-born of these neurons form the deep cortical layers and ultimately project to brainstem and spinal cord. Later-born neurons form the upper layers and ultimately project intracortically. The distinct projection patterns and functional properties of deep- and upper-layer neurons stem from sequential expression of different transcription factors as corticogenesis proceeds. What drives transitions in transcriptional programs is not fully understood, but Toma et al. suggest that intrinsic and extrinsic factors are involved. They found that both deep-layer and upper-layer neurons initially expressed the transcription factor Foxg1, but upper-layer neurons were not produced until a sufficient number of deep-layer neurons were present. If newborn deep-layer neurons were immediately ablated, subsequently born neurons were fated to become deep-layer neurons instead of upper-layer neurons. The authors propose that deep-layer neurons provide negative feedback to Foxg1-lineage cells, ultimately inhibiting acquisition of the deep-layer phenotype and allowing acquisition of the upper-layer phenotype.
Behavioral/Cognitive
p75NTR Limits Cholinergic Innervation of Cortex
Zoran Boskovic, Fabienne Alfonsi, Bree A. Rumballe, Sachini Fonseka, Francois Windels, et al.
(see pages 13033–13038)
Neurotrophins exert opposing effects through different receptors: activation of Trk-family receptors promotes growth and survival, while p75NTR receptors induce axon degeneration and apoptosis. During development, these receptors work together to regulate neuron number and connectivity throughout the nervous system. In most regions, p75NTR expression plummets after the developmental period, but it remains high in cholinergic neurons of the basal forebrain. Continued p75NTR expression inhibits aberrant sprouting of mature cholinergic axons, but the consequences of this for targets has been unclear. Therefore, Boskovic et al. knocked out p75NTR selectively in cholinergic neurons. Consistent with a role for p75NTR in regulating apoptosis during development, more cholinergic neurons were present in mutant mice than in controls. Additionally, cholinergic innervation of the somatosensory cortex was increased in mutant animals. But hippocampal innervation was unaffected and, contrary to some previous results, hippocampal neurogenesis and hippocampus-dependent spatial learning and memory were normal in mutant mice. In contrast, performance on a hippocampus-independent place avoidance test was improved in mutant animals.
Neurobiology of Disease
Knocking Out IKKβ Rescues AD-Like Features in Mice
Yang Liu, Xu Liu, Wenlin Hao, Yann Decker, Robert Schomburg, et al.
(see pages 12982–12999)
Along with amyloid plaques and neurofibrillary tangles, chronic neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia, the brain's resident immune cells, surround β-amyloid (Aβ) deposits and contribute to their clearance. But microglia also secrete neurotoxic cytokines that exacerbate Aβ production. Inhibiting cytokine production may therefore prove beneficial in AD. Cytokine production is activated by the transcription factor NF-κB when its inhibitor (IκB) is phosphorylated by IκB kinase-β (IKKβ). Liu et al. report that knocking out IKKβ selectively in myeloid cells (including microglia) reduced activation of NF-κB. In AD-model mice, IKKβ knockout reduced the number of activated microglia in cortex and hippocampus, reduced levels of inflammatory cytokines and soluble Aβ oligomers, improved performance on a spatial learning test, and rescued reductions in synaptic protein levels. Although the total number of microglia was reduced, more were recruited to Aβ plaques and they expressed higher levels of Aβ scavenger receptor than controls. Moreover, IKKβ-deficient microglia internalized more Aβ oligomers than controls in culture.
