This Week in The Journal

Cellular/Molecular

Microglia Mediate Effects of Exercise on Neurogenesis

Jana Vukovic, Michael J. Colditz, Daniel G. Blackmore, Marc J. Ruitenberg, and Perry F. Bartlett

Much evidence suggests that neurogenesis in the adult dentate gyrus contributes to hippocampus-dependent learning. Blocking neurogenesis impairs such learning, whereas learning enhances survival of adult-born neurons. Furthermore, reduced neurogenesis is associated with age-related cognitive decline. Exercise stimulates neurogenesis and improves cognitive performance, but how it does so is unclear. Vukovic et al. now present surprising evidence that microglia are involved in both exercise-associated enhancement and age-related decline of neurogenesis. Hippocampal cell suspensions from young mice that were allowed to exercise generated more neurospheres containing neural precursors than those from control mice, but this enhancement was reduced when microglia were removed. Moreover, addition of microglia isolated from exercising mice increased neurosphere formation in cultures from sedentary mice. Cultures from old mice generated fewer neurospheres than those from young mice, but neurosphere formation in these cultures was increased by removing microglia. Positive effects of microglia were associated with higher levels of the chemokine CX₃CL1 and required activation of CX₃CL1 receptor CX₃CR1.

Development/Plasticity/Repair

APC2 Is Required for Directional Migration

Takafumi Shintani, Yasushi Takeuchi, Akihiro Fujikawa, and Masaharu Noda

(see pages 6468–6484)

Directional growth and migration require cell surface receptors that, when activated by extracellular guidance molecules, promote assembly, stabilization, or disassembly of actin filaments and/or microtubules. These effects are typically mediated by activation or inactivation of actin-binding and microtubule-associated proteins (MAPs) that alter cytoskeletal dynamics. One such MAP is adenomatous polyposis coli (APC), which promotes microtubule assembly and stabilization and may be involved in the transport of growth-associated proteins. Shintani et al. report that a related protein, APC2, also contributes to directional neuronal migration. Deleting APC2 caused abnormal lamination of cortex, hippocampus, and cerebellum in mice. Surprisingly, however, basal neuronal migration in cultures was unaffected by APC2 deletion: defects appeared only in the presence of gradients of brain-derived neurotrophic factor (BDNF), which failed to stimulate migration of APC2-null neurons. This failure likely stemmed in part from improper trafficking of the BDNF receptor to the leading edge of migrating cells.

In cerebellum of wild-type mice (left), cerebellar granule cells (green) and Purkinje cells (red) are segregated into discrete layers. This pattern is disrupted in mice lacking APC2 (right). See the article by Shintani et al. for details.

Behavioral/Systems/Cognitive

Kidneys Receive Input from Motor Cortex

David J. Levinthal and Peter L. Strick

(see pages 6726–6731)

Kidneys regulate the composition and volume of bodily fluids by removing sodium and waste products from blood and secreting hormones that regulate blood pressure. These functions are regulated by sympathetic innervation, which is activated by signals from chemoreceptors and pressure receptors. But changes in autonomic function can also occur in anticipation of changing needs, and cortical stimulation can activate sympathetic neurons, suggesting there is some high-level control of the autonomic nervous system. Indeed, after injecting a retrograde transneuronal tracer into rat kidney, Levinthal and Strick discovered that fourth-order neurons were present in cortical layer 5, primarily in regions of contralateral motor and premotor cortices (M1 and M2) representing the trunk and hindlimb. With longer periods after virus injection, labeling increased in multiple cortical areas, including somatosensory cortex and prefrontal cortex. These results suggest that an entire visceromotor map exists within M1 and M2.

Neurobiology of Disease

Inhibiting Transglutaminases Is Widely Beneficial

Manuela Basso, Jill Berlin, Li Xia, Sama F. Sleiman, Brendan Ko, et al.

(see pages 6561–6569)

Transglutaminase 2 (TG2) is a multifunctional protein that cross-links proteins via glutamine–lysine transamidation. TG2 has roles in differentiation and wound healing, and it can promote apoptosis or survival under different conditions. Although TG2 activity is normally suppressed in cells, it is induced by increases in intracellular calcium associated with apoptotic stimuli and various stressors. In such cases, protein cross-linking might prevent leakage of harmful cellular components and promote clearance of debris, thus limiting inflammation. Nonetheless, TG2 might stabilize toxic protein oligomers in several neuropathological conditions, and TG2 inhibitors increase survival in models of such diseases. Basso et al. found that expression of both TG1 and TG2 increased in mice subjected to ischemia and in cortical cultures treated with glutamate. Overexpression of either protein killed cultured neurons, whereas TG inhibitors protected neurons from glutamate-induced death. Nonspecific TG inhibitors—including one currently undergoing clinical trials for treatment of Huntington's disease—may therefore be neuroprotective in many neuropathological conditions.