This Week in The Journal

Cellular/Molecular

Cocaine and Its Withdrawal Alter MSN Inhibition and Spiking

Mami Otaka, Masago Ishikawa, Brian R. Lee, Lei Liu, Peter A. Neumann, et al.

Cocaine inhibits the dopamine transporter, thus prolonging activation of dopamine receptors. Elevated dopamine levels produce synaptic and homeostatic plasticity that outlasts the presence of cocaine, and additional plasticity occurs after drug withdrawal and re-exposure. Medium spiny neurons (MSNs) in the nucleus accumbens, which are involved in motivating goal-directed behavior, are important sites of drug-induced plasticity, and modulation of MSN firing is thought to contribute to the development of addiction. How various forms of plasticity are integrated to modify MSN output remains unclear, however. This week, Otaka et al. add a few pieces to the puzzle. In rats allowed to self-administer cocaine for 5 days, the ratio of evoked excitation to evoked inhibition (E/I) in MSNs was reduced, resulting in decreased spiking 1 day after access was denied. The amplitude of miniature (m) IPSCs was reduced after 21 days of withdrawal, but although E/I increased, MSN spiking remained low. Re-exposure to cocaine increased mIPSC frequency, returned evoked E/I to control levels, and increased spiking.

Development/Plasticity/Repair

Bmp7 Promotes Subgranular Zone Expansion by Inducing Lef1

Youngshik Choe, Anastasiia Kozlova, Daniel Graf, and Samuel J. Pleasure

(see pages 6766–6775)

The subgranular zone between the hilus and granule cell layer of the dentate gyrus is one of two sites that produce neurons in adult mammals. This zone is formed by mitotic precursor cells that migrate from the subventricular zone at the earliest stages of dentate development. These precursors produce the neurons that form the inner granule cell layers of the dentate, and they continue to generate neurons throughout life. Two critical players in dentate development are the secreted protein Wnt3a and its downstream transcription factor Lef1: Wnt3a-null mice lack hippocampi, and Lef1-null mice have few granule cells. Choe et al. now report that bone morphogenic protein 7 (Bmp7) feeds into this pathway by inducing Lef1 expression. Ectopic expression of Bmp7 in the medial cortical wall increased the production of dentate granule cells during embryogenesis, whereas decreasing meningeal expression of Bmp7 reduced numbers of Lef1-positive cells, proliferating precursors, and postmitotic granule cells in the developing dentate gyrus.

Inhibiting Bmp7-induced signaling in dentate precursor cells on postnatal day 1 (bottom) reduces the number of cells expressing Lef1 (green) and a marker of dentate granule cells (red) compared to controls (top). See the article by Choe et al. for details.

Behavioral/Cognitive

Mice Localize Objects by Sensing Whisker Bending and Pushing

Lorenz Pammer, Daniel H. O'Connor, S. Andrew Hires, Nathan G. Clack, Daniel Huber, et al.

(see pages 6726–6741)

As a rodent's whisker presses against an object, the whisker bends, pushes laterally against the side of the whisker follicle, and pushes axially into the follicle. Because whiskers are tapered, the stresses produced in the follicle change at different rates depending on where the object contacts the whisker. Stresses within follicles activate mechanoreceptors, and rodents use differential activation of these receptors to discern object shape and distance. Pammer et al. found that head-fixed mice could discriminate object positions differing by as little as 1 mm with a single whisker. To determine which mechanical variables are important for discriminating radial distance, they analyzed high-speed video recordings to estimate the bending moment, lateral force, and axial force produced at the base of whiskers by rigid and compliant objects placed at different positions. Their results suggest that mice use multiple variables—in particular, relative rates of change in bending moment and axial force—to determine object distance.

Neurobiology of Disease

SorCS1 Mutations Disrupt APP Trafficking

Rachel F. Lane, John W. Steele, Dongming Cai, Michelle E. Ehrlich, Alan D. Attie, et al.

(see pages 7099–7107)

Amyloid precursor protein (APP) and the secretases that cleave it are transmembrane proteins that are processed, sorted, and trafficked through membranous organelles. Sequential cleavage of APP to generate Aβ is likely to occur in the endocytic pathway, and accumulating evidence suggests that defects in membrane trafficking in this pathway promote formation of Aβ42, the oligomerization-prone peptide implicated in Alzheimer's disease (AD). Several proteins involved in membrane trafficking have been linked to AD, including SorCS1, which associates with APP and influences Aβ production. SorCS1 has been proposed to regulate either internalization of APP from the plasma membrane or trafficking of APP from endosomes to the trans-Golgi network (TGN). Lane et al. present data supporting the latter hypothesis. A mutation in the cytoplasmic tail of SorCS1c increased its plasma membrane levels without affecting those of APP. And another SorCS1c mutation increased levels of APP cleavage products in enlarged endosome-like compartments, reduced levels of these fragments in the TGN, but did not alter plasma membrane levels.