This Week in The Journal

Cellular/Molecular

Cortactin-Binding Protein Regulates Cortactin Distribution

Yi-Kai Chen and Yi-Ping Hsueh

Cortactin is an actin-binding protein that stabilizes actin filaments and plays a role in endocytosis. Cortactin is enriched in dendritic spines, but NMDA receptor activation causes it to move from spines into the dendritic shaft, suggesting it contributes to neuronal plasticity, possibly by allowing remodeling of spine morphology. Indeed, knockdown of cortactin reduces spine density in cultured hippocampal neurons. Chen and Hsueh propose that cortactin distribution in neurons is regulated by cortactin-binding protein 2 (CTTNBP2). They found that CTTNBP2 was enriched in dendritic spines in cultured rat hippocampal neurons, but unlike cortactin and actin, CTTNBP2 remained in spine heads after glutamate treatment. Knockdown of CTTNBP2 reduced spine density, reduced levels of cortactin in remaining spines, and decreased the frequency of miniature EPSCs recorded in cultured hippocampal neurons. Spine density was rescued by expression of siRNA-resistant CTTNBP2 or overexpression of cortactin, but not by a mutated form of CTTNBP2 that could not bind to cortactin.

Under normal conditions (left), CTTNBP2 (top), actin (middle), and cortactin (bottom) are concentrated in spines of cultured hippocampal neurons. NMDA treatment (right) causes actin and cortactin, but not CTTNBP2, to move into the shaft. See the article by Chen and Hsueh for details.

Development/Plasticity/Repair

Adult Zebra Finch HVC Gains Neurons throughout Life

Clare Walton, Eben Pariser, and Fernando Nottebohm

(see pages 761–774)

Neurogenesis occurs in adults of many species, but its function is unclear. In seasonally breeding songbirds, the size of the high vocal center (HVC)—a region that influences the temporal order of syllables during singing—varies seasonally as a result of ongoing neuronal death and neurogenesis. This fluctuation was originally identified in canaries, which learn new songs during the fall when neuron addition peaks, and it was hypothesized to facilitate song alteration. But similar fluctuations also occur in species that sing the same song every spring. In these species, the song becomes more variable during non-breeding seasons, suggesting that the neurons lost and recruited contribute to song stability and maintenance. Walton et al. now report that zebra finches—which sing the same song throughout the year—also add HVC neurons throughout life, but without significant neuronal loss. Thus, the number of neurons in HVC doubles over the adult lifespan. The function of this neurogenesis remains a mystery.

Behavioral/Systems/Cognitive

Dyslexia-Linked ROBO1 Mutation Affects Auditory Processing

Satu Lamminmäki, Satu Massinen, Jaana Nopola-Hemmi, Juha Kere, and Riitta Hari

(see pages 966–971)

Dyslexia often results from deficits in the auditory processing required to distinguish phonemes in speech. This makes it difficult to relate written letters to phonemes, to combine letters into syllables, and therefore to learn to read. Dyslexia has a strong genetic component, and most of the genes proposed to cause the deficit are involved in neuronal migration or axon guidance. One such gene is ROBO1, which regulates midline crossing by axons. Lamminmäki et al. studied a family in which mutations that reduce ROBO1 expression are linked to dyslexia. To determine whether the mutation affects midline crossing, they measured binaural suppression, a reduction in auditory cortical responses to inputs from the ipsilateral ear that occurs when auditory stimuli are presented binaurally. This suppression depends on fibers crossing from the contralateral auditory cortex. Binaural suppression was greatly reduced in subjects harboring the abnormal ROBO1 haplotype, and the reduced suppression was correlated with ROBO1 expression level.

Neurobiology of Disease

AMP Kinase Knockdown Attenuates Effects of SOD1 Mutation

M. A. Lim, M. A. Selak, Z. Xiang, D. Krainc, R. L. Neve, et al.

(see pages 1123–1141)

Mitochondrial dysfunction occurs in many neurodegenerative diseases. For example, amyotrophic lateral sclerosis (ALS) is sometimes caused by mutations in superoxide dismutase 1 (SOD1) that increase the protein's association with mitochondria, thus disrupting ATP production. Reductions in ATP/AMP ratios activate AMP kinase (AMPK), which initiates programs to increase energy supplies, such as increasing fatty acid oxidation and glucose uptake. But AMPK also activates pathways that conserve energy, e.g., by reducing protein synthesis. These processes might be detrimental to neurons and thus contribute to neuropathology. Indeed, Lim et al. found that expression of mutant SOD1 in rodent spinal cord neurons reduced mitochondrial respiration, increased activity of AMPK and an AMPK target that stimulates fatty acid oxidation, and reduced activity of an AMPK target that regulates protein translation. Knocking down AMPK greatly increased survival of neurons expressing mutant SOD1. Similarly, expressing mutant SOD1 in worms impaired locomotion, which was rescued by coexpressing nonfunctional AMPK.