Development/Plasticity/Repair
mGluR Antagonist Rescues Auditory Plasticity in Fmr1-Null Mice
Heesoo Kim, Robert Gibboni, Colleen Kirkhart, and Shaowen Bao
(see pages 15686–15692)
Fragile X syndrome, the most common hereditary form of mental retardation, is caused by loss-of-function mutations in Fmr1, the gene that encodes Fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that regulates local translation of several synaptic proteins, thus influencing synaptic plasticity. In particular, FMRP is thought to limit the development of long-term depression (LTD) by repressing protein translation triggered by metabotropic glutamate receptor (mGluR) activation. In mice, loss of FMRP leads to excessive LTD along with an overabundance of immature dendritic spines and abnormal activity-dependent plasticity in visual and somatosensory cortex. Kim et al. now report that auditory plasticity is also defective in Fmr1-null mice. Exposing wild-type mice to a 16 kHz tone during the auditory critical period caused expansion of the cortical area representing this frequency and reduced representation of nearby frequencies. Such functional remapping did not occur in Fmr1-null mice. Remapping was rescued, however, if mice were treated with an mGluR antagonist during the critical period.
Systems/Circuits
Neurons Expressing dNPF Encode Food Odor Value in Flies
Jennifer Beshel and Yi Zhong
(see pages 15693–15704)
Why are some smells appealing and others disgusting? Although the neural basis of odor valuation in mammals is unknown, Beshel and Zhong have identified neurons that encode food-odor value in the protocerebrum of Drosophila. The amplitude of odor-elicited activity in four large neurons that express neuropeptide F (dNPF) was strongly correlated with the attractiveness of odors in behavioral tests. This correlation held not only across food odors but also across motivational states: attractive odors were even more attractive and elicited greater activity in dNPF neurons when flies were hungry than after they were fed. Inhibiting dNPF neurons or knocking down dNPF receptors eliminated approach to even the most attractive food odor in starved flies, whereas activating the neurons increased approach to mildly attractive and even aversive odors. Finally, the relative activity levels elicited by two food odors predicted which one flies would approach when both were presented, and because odor-evoked activity varied with concentration, manipulating odor concentration altered the choice.
Behavioral/Cognitive
Cocaine Shifts Balance of D1 and D2 Receptor Pathways
Kicheon Park, Nora D. Volkow, Yingtian Pan, and Congwu Du
(see pages 15827–15836)
Like most abused drugs, cocaine promotes dopamine signaling in the striatum. Cocaine's rewarding effects result largely from activation of medium spiny neurons that express D1 dopamine receptors (D1R-MSNs). Activation of neurons expressing D2 receptors (D2R-MSNs), in contrast, reduces cocaine reward. The development of cocaine addiction has therefore been hypothesized to involve an increase in the cocaine-induced activation of D1R-MSNs relative to D2R-MSN activation. To test this hypothesis, Park et al. used calcium imaging to monitor activity of striatal MSNs after acute cocaine administration in naïve mice and mice chronically exposed to cocaine. Cocaine reduced Ca2+ concentration ([Ca2+]) in D2R-MSNs of both groups of mice, but baseline levels were lower in D2R-MSNs of chronically treated mice. Cocaine increased [Ca2+] in D1R-MSNs, and although the onset of [Ca2+] elevation was faster in D1R-MSNs of naïve mice, [Ca2+] continued to rise for much longer in chronically treated mice. Consequently, cocaine induced a longer-lasting increase in the ratio of D1R-MSN to D2R-MSN activity in chronically treated mice.
Neurobiology of Disease
Loss of Filamin A Disrupts Transport of Big2
Jingping Zhang, Jason Neal, Gewei Lian, Jianjun Hu, Jie Lu, et al.
(see pages 15735–15746)
Cell migration requires coordination of several cellular processes, including reorganization of the actin cytoskeleton to allow changes in cell shape; formation and removal of cell adhesions at the leading and trailing edges of the cell, respectively; and endocytosis, transport, and exocytosis of vesicles that supply membrane components to the extending leading edge. The actin-binding protein Filamin A regulates the integrity of the submembrane actin network and helps form adhesions between the actin cytoskeleton and the substrate. Loss of Filamin A impairs migration of neuroblasts in humans, causing periventricular heterotopia, in which neuronal nodules form along the ventricular neuroepithelium. Zhang et al. propose that loss of Filamin A not only affects migration by disrupting formation of actin filaments, but also by indirectly disrupting vesicle trafficking through interactions with another protein linked to periventricular heterotopia, Big2. Knockout of Filamin A reduced translocation of Big2 from the Golgi apparatus to the periphery, where it normally activates Arf1, a membrane-associated GTP-binding protein that regulates vesicular trafficking, adhesion formation, and actin remodeling.
Migrating neural progenitors normally extend processes supported by actin filaments (green) shortly after plating onto coverslips (left). Process extension is reduced in progenitors lacking Filamin A (right), which fail to migrate properly. See the article by Zhang et al. for details.
