This Week in The Journal

Cellular/Molecular

CREB3L1 Regulates Arginine Vasopressin Expression

Mingkwan Greenwood, Loredana Bordieri, Michael Greenwood, Mariana Rosso Melo, Debora S. A. Colombari, et al.

Arginine vasopressin (AVP) is synthesized in the supraoptic (SON) and paraventicular (PVN) nuclei of the hypothalamus and stored in the posterior pituitary. When plasma osmolarity increases because of dehydration or high salt intake, AVP is secreted into the blood; it reduces water loss by constricting blood vessels and increasing water reabsorption in the kidneys. Chronic hyperosmolarity increases AVP expression, but the responsible molecular pathways are poorly understood. Greenwood et al. now demonstrate that AVP transcription is regulated by CREB3L1, a transcription factor that is upregulated in SON and PVN during dehydration. Dehydration and salt-loading caused parallel increases—whereas salt depletion caused decreases—in CREB3L1 mRNA and AVP mRNA in rat SON and PVN neurons. Furthermore, CREB3L1 directly binds to the AVP promoter. CREB3L1 drove expression of a protein under control of the AVP promoter in HEK263T cells, whereas expression of a dominant-negative CREB3L1 reduced protein expression. Finally, overexpression of constitutively active CREB3L1 in SON and PVN increased levels of AVP in the pituitary.

Expression of CREB3L1 (green) is higher in AVP-expressing neurons (red) in dehydrated rats (right) than in controls (left). See the article by Greenwood et al. for details.

Development/Plasticity/Repair

TrkA Signaling Levels Are Reduced by Ubiquitylation

Erkan Kiris, Ting Wang, Sudhirkumar Yanpallewar, Susan G. Dorsey, Jodi Becker, et al.

(see pages 4090–4098)

Ubiquitylation is a posttranslational modification that involves attaching a ubiquitin protein to a specific site on a different protein. Although ubiquitylation is best known for its role in targeting proteins for degradation, it can also regulate protein interactions and activity. Investigating the role of a three-amino-acid sequence (KFG) present in neurotrophin-binding tyrosine-kinase receptors of the Trk family, Kiris et al. were surprised to discover that deletion of this domain increased TrkA protein levels, but not mRNA levels. Further investigation revealed that KFG removal prevented ubiquitylation of TrkA and caused internalized TrkA receptors to return to the plasma membrane instead of being degraded. Activation of TrkA by its ligand, nerve growth factor (NGF), and activation of downstream signaling molecules were higher in cells expressing mutant TrkA than in cells expressing wild-type TrkA. And because NGF–TrkA signaling has roles in nociception, mice expressing TrkA receptors that lacked the ubiquitylation domain were more sensitive to noxious heat and inflammatory pain than wild-type animals.

Systems/Circuits

Narrow Thorny RGCs Project to Koniocellular Layer K1

Kumiko A. Percival, Amane Koizumi, Rania A. Masri, Péter Buzás, Paul R. Martin, et al.

(see pages 3821–3825)

Visual information is processed in parallel pathways starting in the retina. In the lateral geniculate nucleus, these parallel pathways are spatially segregated in the magnocellular layer, which receives inputs from parasol retinal ganglion cells (RGCs); the parvocellular layer, which receives inputs from midget RGCs; and intercalated koniocellular layers, which are thought to receive inputs from RGCs with wide dendritic fields. In marmosets, koniocellular layer K3 receives inputs primarily from small bistratified RGCs that transmit information from short-wavelength-sensitive (“blue”) cones. Percival et al. provide evidence that koniocellular layer K1 receives inputs from narrow thorny RGCs—cells characterized by highly branched dendrites with numerous spines—which receive inputs predominantly from DB6 diffuse bipolar cells. The response properties of narrow thorny RGCs is unknown, but based on the properties of K1 cells, the authors suggest this pathway is specialized for motion processing; and because K1 projects directly to the direction-sensitive cortical area MT, this pathway might underlie residual visual function (“blindsight”) that persists after primary visual cortex is damaged.

Neurobiology of Disease

Overexpression of Precursor, Not β-Amyloid, Causes Seizures

Heather A. Born, Ji-Yoen Kim, Ricky R. Savjani, Pritam Das, Yuri A. Dabaghian, et al.

(see pages 3826–3840)

People with Alzheimer's disease (AD), particularly those with early-onset familial forms, have more seizures than the general population. Transgenic mice overexpressing AD-linked forms of amyloid precursor protein (APP) also have spontaneous seizures, as well as abnormal sharp wave discharges (SWD) detected by electroencephalography. β-Amyloid (Aβ), a probable cause of cognitive decline in AD, increases activity in excitatory neurons, which might lead to seizures. Surprisingly, however, Born et al. found that inhibiting Aβ generation from APP did not reduce SWD frequency in APP-overexpressing mice. SWD frequency was decreased to control levels when overexpression of APP was suppressed, however. APP overexpression also increased cortical expression of glutamate transporters and lowered expression of GABA transporters, and these changes were not rescued by inhibiting Aβ production. Moreover, in transgenic mice in which Aβ production was increased without overexpressing APP, SWD frequency was similar to wild-type. Therefore, overproduction of either APP itself or a cleavage product other than Aβ appears to cause seizures in AD mice.