Lighting Up FMRP Protein Expression
Lisa A. Gabel, Sandra Won, Hideki Kawai, Margaret McKinney, Alan M. Tartakoff, and Justin R. Fallon
(see pages 10579-10583)
The most common form of inherited mental retardation, Fragile X syndrome (FXS), results from triplet repeat expansion in the Fmr1 gene, leading to loss of Fragile X mental retardation protein (FMRP) expression. Normally, FMRP binds to and represses translation of mRNAs, including those expressed in dendrites and near synapses. Adding to the idea that FMRP is important for synaptic plasticity, mice lacking FMRP show deficient cortical long-term potentiation, enhanced hippocampal long-term depression, and abnormal dendritic spines. In this issue, Gabel et al. report that FMRP expression is dynamically regulated in vivo in dark-reared, light-exposed rats. In visual cortical neurons, FMRP expression increased after only 15 min of visual experience and quickly returned to baseline. Blocking NMDA receptors prevented the upregulation. The protein localized to cell bodies, dendrites, and synaptic fractions, consistent with a role in synaptic plasticity. Interestingly, the regulation was post-transcriptional, because FMRP mRNA levels remained constant, suggesting that the increased levels might be attributable to altered degradation of FMRP.
Teasing Apart CaMKII-Dependent Behavior
Jennifer E. Mehren and Leslie C. Griffith
(see pages 10584-10593)
The conversion of calcium/calmodulin-dependent protein kinase II (CaMKII) from inactive to active by autophosphorylation is much discussed as a molecular switch in synaptic plasticity. This week Mehren and Griffith compared the roles of calcium-dependent and -independent forms of CaMKII in flies. They used a courtship training paradigm in which male flies court mated females and pheromonal cues from the females suppress courtship. In subsequent trials with virgin females, the trained male flies also show suppressed courtship. Apparently, for flies at least, rejection is a powerful learning experience. The authors manipulated the expression of two forms of CaMKII: a calcium-independent and constitutively active form (T287D) or a strictly calcium-dependent form (T287A). After training, wild-type flies displayed a lag before suppression of courtship behavior that was absent in T287D-expressing flies. The results suggest a threshold requirement for calcium-independent CaMKII in this learned behavior, specifically in antennal lobe and mushroom body neurons.
Neurogranin and Synaptic Plasticity
Kuo-Ping Huang, Freesia L. Huang, Tino Jäger, Junfa Li, Klaus G. Reymann, and Detlef Balschun
(see pages 10660-10669)
Location is everything in calcium signaling. Thus proteins that bind calcium, or calcium-binding proteins, are potential regulators of neuronal signaling. Neurogranin (Ng), a 78 aa peptide, is interesting in this regard. It binds calmodulin and, when phosphorylated, it enhances mobilization of calcium from internal stores. When bound to Ng, calmodulin is less apt to complex with calcium or calcium/calmodulin-dependent protein kinase II. Phosphorylation by protein kinase C also reduces Ng binding to calmodulin. This week, Huang et al. compared mice with two copies, one copy, or no copies of the Ng gene. Knock-out mice displayed impaired spatial learning (in a Morris water maze task), reduced long-term potentiation, and small calcium transients in CA1 pyramidal cells. The authors conclude that Ng normally buffers calmodulin, thereby increasing free intracellular calcium and boosting calcium-dependent synaptic potentiation. Wild-type hippocampal neurons and dendrites expressed Ng at a much higher concentration than calmodulin, supporting such a “mass-action” mechanism.
Neurobiology of Disease
Neural Progenitor Cell Transplants in Niemann-Pick Mice
L. S. Shihabuddin, S. Numan, M. R. Huff, J. C. Dodge, J. Clarke, S. L. Macauley, W. Yang, T. V. Taksir, G. Parsons, M. A. Passini, F. H. Gage, and G. R. Stewart
(see pages 10642-10651)
Without acid sphingomyelinase (ASM), lysosomes accumulate excess sphingomyelin and cholesterol, resulting in the inherited type-A Niemann-Pick disease (NPD-A), a fatal childhood disorder with enlarged organs and neurodegeneration. Various therapeutic approaches have been tried in such storage diseases, and now neural progenitor cells (NPCs) are taking center stage. This week Shihabuddin et al. isolated NPCs from adult mouse forebrain and transduced them with a retroviral vector driving overexpression of human ASM (hASM). Once transplanted into the brains of mice lacking the ASM gene, the engineered cells migrated away from the injection site, differentiated into neurons, and survived for up to 10 weeks. In vitro, ASM activity released from gene-modified NPCs was fivefold higher than controls. Although immunostaining detected only low levels of hASM in vivo, PCR showed expression of ASM mRNA, and, most importantly, pathological accumulation of cholesterol was reduced, at least in the region to which the NPCs migrated. It's encouraging, but hurdles remain before this can become a treatment strategy for this disorder.