Cellular/Molecular
cAMP and a Retinal Clock
Chiaki Fukuhara, Cuimei Liu, Tamara N. Ivanova, Guy C.-K. Chan, Daniel R. Storm, P. Michael Iuvone, and Gianluca Tosini
(see pages 1803-1811)
In photoreceptors, an autonomous circadian clock interacts with the light/dark cycle to control aspects of retinal function. The circadian pattern of melatonin synthesis in photoreceptors is regulated by arylalkylamine N-acetyltransferase (AA-NAT). Transcription of AA-NAT is under dual control by CLOCK and BMAL1 transcription factors at an E-box transcriptional site, and by a cAMP:cAMP response element (CRE)-mediated site. Fukuhara et al. now report that the gene for type 1 adenylyl cyclase (AC1) also contains an E-box site, and it too is controlled by the CLOCK:BMAL1 complex. The clock genes exerted rhythmic control of AC1 expression, and thus cAMP synthesis, in the retina as well as in the pineal gland and suprachiasmatic nucleus. Because AC1 is calcium dependent, the nighttime increase in photoreceptor cytoplasmic calcium, induced by the depolarizing dark current, increases cAMP and thus melatonin synthesis. The authors suggest that clock control of cAMP signaling may serve a general role in the integration of circadian signals.
Development/Plasticity/Repair
p75: Lessons from a Knock-Out That Wasn't a Knock-Out
Christine E. Paul, Emily Vereker, Kathleen M. Dickson, and Philip A. Barker
(see pages 1917-1923)
The p75 neurotrophin receptor (p75NTR) remains an enigma. It binds all neurotrophins and can activate seemingly opposing signaling cascades. Several transgenic mouse models have been created to address the function of p75NTR in vivo. An exon III-/- mouse expresses no full-length protein but was later found to produce a spliced isoform lacking the external neurotrophin-binding site. More recently, a mouse with a mutation in exon IV was thought to be entirely p75NTR deficient, but it now appears that its high mortality and severe defects may result in part from an unexpected gain-of-function. Paul et al. identified a 26 kDa protein in exon IV-/- mice that contains the transmembrane and intracellular domains of p75NTR. Transcription of the fragment was driven by a sequence within the inserted pGK-Neo cassette in exon IV. Overexpression of the fragment activated p75NTR-mediated signaling cascades leading to apoptosis. The exon IV-/- mouse, although perhaps not the true null it was thought to be, may still help reveal the complex signaling of p75NTR.
Behavioral/Systems/Cognitive
Motivation, the Brain, and the Adolescent
James M. Bjork, Brian Knutson, Grace W. Fong, Daniel M. Caggiano, Shannon M. Bennett, and Daniel W. Hommer
(see pages 1793-1802)
What motivates teenagers is a question that can baffle parents and teachers. Physical differences in the motivational circuit of the ventral striatum have been suggested as underlying the tendency of some teens to take risks without fully considering the consequences. Does risk-taking result from an “overactive” motivational circuitry or from a hypoactive circuit that requires high-risk/high-reward incentives? In this week's Journal, Bjork et al. compared teen and adult brain activity in the ventral striatum during a money-motivated game. In all subjects, anticipation of monetary gain (20 cents, $1, or $5) caused activation of the ventral striatum, whereas notification of gain activated the mesial frontal cortex. However, teens aged 12-17 showed less activation in the right nucleus accumbens in anticipation of monetary gain than did young adults. The authors suggest that adolescents show reduced recruitment of motivational reward-directed behavior. Okay, but maybe the authors should have tried $20!
Blood oxygen level-dependent (BOLD) signals in subjects who were anticipating responding for monetary gain. Signals in the ventral striatum were bilaterally enhanced in adults (B) compared with adolescents (A).
Neurobiology of Disease
Friedreich Ataxia in the Mouse
Delphine Simon, Hervé Seznec, Anne Gansmuller, Nadège Carelle, Philipp Weber, Daniel Metzger, Pierre Rustin, Michel Koenig, and Hélène Puccio
(see pages 1987-1995)
Friedreich's ataxia (FRDA) is named for the resulting progressive balance deficits and sensory neuropathy, but it is also associated with diabetes and cardiomyopathy. The disease is most commonly caused by GAA triplet expansion in the first intron of frataxin, leading to reduced transcription. Frataxin is a mitochondrial protein that is involved in iron-sulfur complex (ISC) assembly. Reduced function of the ISC can cause oxidative stress and iron accumulation. Although the cellular effects have been studied in yeast, an animal model would facilitate studies of disease mechanisms. Because frataxin-deficient mice do not survive long enough to allow detailed study, Simon et al. created two conditional, neuron-specific knock-out mice. The mice have a normal life expectancy, but they show ataxia and progressive sensory loss as in FRDA. The death of large sensory neurons in the dorsal root ganglia appeared to be autophagic rather than apoptotic. These mice should help unravel the pathophysiology of FRDA.
