Cellular/Molecular
Regulating Proteasomal Gene Expression
Allan B. James, Ann-Marie Conway, and Brian J. Morris
(see pages 1624–1634)
At first glance, the proteasome, the multiprotein complex that targets cellular proteins for degradation, might not seem like the place to look for plasticity-related genes. However, inhibition of proteasomal activity has been shown to affect neuronal plasticity. This week James et al. make a case for a link between proteasomal gene expression and the activity-dependent transcription factor Zif268. The authors first used microarrays to look for Zif268-regulated genes. Overexpression of Zif268 in PC12 cells suppressed mRNA levels of the proteasomal subunits psmb9 and psme2 as well mRNA of regulatory proteins like serum/glucocorticoid-regulated kinase (SGK). The promoter sequence of these genes contained consensus Egr response element (ERE) sites that bind Zif268. In neurons of Zif268 knock-out mice, mRNA of the targeted genes and cortical proteasome activity increased. In vivo haliperidol administration, an established means to induce synaptic plasticity in the striatum, rapidly increased Zif268 mRNA and produced more complex changes in proteasomal gene expression.
Development/Plasticity/Repair
The Layering of Interneurons
Vicki Hammond, Eva So, Jenny Gunnersen, Helen Valcanis, Michael Kalloniatis, and Seong-Seng Tan
(see pages 1646–1655)
This week Hammond et al. explored the layer distribution of cortical interneurons in mice that lacked components of the Reelin signaling pathway. The results suggest that early- and late-born interneurons follow different sets of cues in reaching their final position. The authors argue that early-born interneurons follow the layering of projection neurons whereas late-born interneurons rely on Reelin signaling. Early-born interneurons (E12.5 or E13.5) were predominantly distributed in lower cortical layers. However, in mice lacking reelin or disabled-1 (Dab1) the layering was inverted, as if following the pattern of projection neurons. In contrast late-born interneurons (E15.5 or 16.5) in these mice showed an apparently random cortical distribution. In mice lacking p35, in which Reelin signaling remains intact but pyramidal neuron layers are inverted, late-born interneuron distribution approximated normal wild-type layering, but early-born interneurons were inverted along with projection neurons. Transplantation of Dab1-expressing, late-born interneurons into a Dab1−/− mouse rescued correct interneuronal positioning.
Behavioral/Systems/Cognitive
Interpreting Arc Expression in the Hippocampus
Bonnie R. Fletcher, Michael E. Calhoun, Peter R. Rapp, and Matthew L. Shapiro
(see pages 1507–1515)
This week Fletcher et al set out to determine whether induction of the immediate early gene Arc is specifically linked to hippocampal learning or just reflects behaviorally induced neuronal activity. The authors used a novel water maze task to separate spatial learning that requires hippocampal activity from cue-approach learning that does not. They also made fornix lesions that interrupt connections between the hippocampus and subcortical regions and impair hippocampal-dependent learning. On a water maze task, lesioned and sham-lesioned rats learned to approach a visible platform to escape a water maze (cue-approach learning) but lesioned rats were unable to learn the spatial location when the platform was hidden. Hippocampal expression of Arc was significantly elevated in sham-lesions rats after exploration after water maze. In contrast, fornix-lesioned animals did not show Arc expression following water maze training. The authors argue that Arc expression reflects activation of synaptic plasticity mechanisms.⇓
Pseudocolored autoradiographs demonstrate Arc mRNA expression in the stimulated ipsilateral, but not the unstimulated contralateral hippocampus of sham and lesion animals. See the article by Fletcher et al. for details.
Neurobiology of Disease
Calcineurin Inhibition and Huntingtin Toxicity
Raúul Pardo, Emilie Colin, Etienne Réegulier, Patrick Aebischer, Nicole Déeglon, Sandrine Humbert, and Fréedéeric Saudou
(see pages 1635–1645)
In vitro, the toxicity of the triplet-repeat protein huntingtin appears to be affected by its phosphorylation state. The serine/threonine kinase Akt and the serum and glucocorticoid-induced kinase (SGK) phosphorylate huntingtin at serine 421 (S421). This week Pardo et al. explore whether block of dephosphorylation might have therapeutic potential in rodent models of Huntington’s disease. The authors report that lesions associated with overexpression of a polyglutamine-huntingin fragment with 68 glutamines were larger in S421A mutants that cannot be phosphorylated, suggesting that phosphorylation affects the huntingtin-mediated toxicity. To examine the relevant phosphatases, the authors used in vitro methods. The calcium/calmodulin-dependent phosphatase calcineurin (CaN) dephosphorylated the S421 site in cultured striatal cells. A dominant-negative CaN decreased polyQ-mediated toxicity and the immunosuppressant drug FK506 blocked CaN-mediated dephosphorylation. In cells expressing polyQ huntingtin, treatment with FK506 increased S421 phosphorylation and reduced cell death. Oral or intraperitoneal FK506 increased S421 phosphorylation, opening the door for further tests of this hypothesis.
