Cellular/Molecular
Increases in MMP-9 Underlie Several Effects of FMRP Loss
Harpreet Sidhu, Lorraine E. Dansie, Peter W. Hickmott, Douglas W. Ethell, and Iryna M. Ethell
(see pages 9867–9879)
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that transports mRNAs into dendrites and regulates their translation. FMRP is thought to repress local translation of synaptic proteins in the absence of regulatory signals such as synaptic activity. Loss of FMRP allows excessive translation to occur in the absence of synaptic activity, and it causes mental retardation and autism in fragile X syndrome (FXS). One protein regulated by FMRP is matrix metalloproteinase 9 (MMP-9), which, after activity-dependent synthesis and secretion, cleaves extracellular proteins and thus influences synaptic remodeling. MMP-9 levels are elevated in FMRP-null mice, and this likely contributes to the overabundance of long, thin dendritic spines in these mice. In fact, Sidhu et al. provide evidence that overexpression of MMP-9 contributes to several FXS-like phenotypes in FMRP-null mice. In addition to rescuing spine morphology, knocking out MMP-9 rescued hyperactivity, social avoidance or indifference, enhancement of long-term depression induced by metabotropic glutamate receptor agonists, and testicular enlargement in FMRP-null mice.
Systems/Circuits
Leptin Depolarizes Orexigenic Neurons in Neonatal Mice
Arian F. Baquero, Alain J. de Solis, Sarah R. Lindsley, Melissa A. Kirigiti, M. Susan Smith, et al.
(see pages 9982–9994)
Appetite is regulated by the opposing actions of two groups of hypothalamic neurons: neurons that coexpress neuropeptide Y, agouti-related peptide, and GABA (NAG neurons), which promote feeding; and neurons expressing proopiomelanocortin peptide (POMC), which suppress feeding. In adult mice, leptin, secreted by fat cells, inhibits NAG neurons and activates POMC neurons, thus reducing feeding. Although leptin levels are high in neonatal mice and leptin acts on neonatal NAG neurons to promote axon growth, leptin does not suppress feeding in neonatal mice. Baquero et al. asked why this is the case. They identified two likely contributors. First, leptin receptors were not expressed on most POMC neurons until weaning, near the end of the third week. More interestingly, leptin depolarized NAG neurons in early neonates, suggesting it may actually stimulate feeding. Leptin's ability to hyperpolarize NAG neurons developed gradually after the third postnatal week, and the early depolarizing effect was attributable to the lack of ATP-sensitive potassium channels—which underlie leptin-induced hyperpolarization—in neonatal NAG neurons.
Behavioral/Cognitive
Reducing Cochlear Amplification May Help Shift Attention
Anna Wittekindt, Jochen Kaiser, and Cornelius Abel
(see pages 9995–10002)
In the mammalian cochlea, most stimulus energy would be lost to viscous fluid drag and absorption by hair cells if it weren't for the motile forces generated by outer hair cells (OHCs). Instead, the mechanical amplification provided by OHCs greatly enhances auditory sensitivity and discrimination. The amount of this amplification can be modulated by inputs to OHCs from medial olivocochlear projections, and Wittekindt et al. now demonstrate that such modulation contributes to selective attention. Cochlear amplification was assessed by measuring distortion-product otoacoustic emissions (DPOAEs): sounds produced when vibrations generated by OHCs are transmitted to the base of the cochlea, causing the tympanum to vibrate. The DPOAE level elicited by simultaneously presented tones decreased when human participants' attention was focused on a concurrent visual stimulus. In contrast, no change in DPOAE level occurred when subjects focused on auditory stimuli. This suggests that suppression of cochlear amplification is used to reduce distraction from irrelevant auditory stimuli when one attends to visual stimuli.
Neurobiology of Disease
β-Spectrin Mutations Disrupt Glutamate Receptor Clustering
Karen R. Armbrust, Xinming Wang, Tyisha J. Hathorn, Samuel W. Cramer, Gang Chen, et al.
(see pages 9891–9904)
Spinocerebellar ataxias (SCAs) are a large, genetically diverse group of autosomal dominant diseases in which degeneration of cerebellar neurons causes loss of coordination. SCA5 is a relatively minor form of SCA caused by mutations in β-III spectrin, a cytoskeletal protein that helps anchor transmembrane proteins. To investigate how such mutations cause Purkinje cells to degenerate, Armbrust et al. generated a transgenic mouse that expressed an SCA5-linked form of β-III spectrin selectively in these cells. Like SCA5 patients, mice expressing mutant β-III spectrin showed progressive loss of coordination and cerebellar degeneration. Both wild-type and mutant β-III spectrin interacted with metabotropic glutamate receptor type 1α (mGluR1α), but the SCA5-linked mutation disrupted the ability of β-III spectrin to stabilize and cluster mGluR1α in the plasma membrane of dendritic spines. Likely as a result, the mGluR1α-mediated response to parallel fiber stimulation was reduced, and long-term potentiation induced by high-frequency burst stimulation of parallel fibers was virtually eliminated in mutant mice.
In normal mice (top), mGluR1α (red) clusters at dendritic spines in Purkinje cells (green). Expression of β-III spectrin harboring SCA5-linked mutations (bottom) reduced this clustering. See the article by Armbrust et al. for details.