FMRP and the Polyribosome
Giovanni Stefani, Claire E. Fraser, Jennifer C. Darnell, and Robert B. Darnell
(see pages 7272-7276)
Fragile X mental retardation syndrome affects one of every 4000 males as a result of silencing of a gene encoding an RNA-binding protein. The FMR1 gene product, fragile X mental retardation protein (FMRP), associates with polyribosomes in non-neuronal cells, suggesting that its normal function is regulation of protein translation. However, FMRP association with polyribosomes has not been demonstrated in brain tissue. Now, Stefani et al. report that in cortical extracts from mice, FMRP cosediments with polyribosomes. Furthermore, in cultured neuroblastoma cells, puromycin, which specifically disrupts active translating ribosomes, disrupted large FMRP-polyribosome complexes. These studies support the idea that FMRP regulates protein translation, but many questions remain. For example, how does it affect translation and is the net effect of FMRP enhanced or depressed translation? The authors suggest that FMRP might affect translation of mRNAs already engaged in polyribosomes, perhaps making them suitable for regulation of protein synthesis-dependent synaptic plasticity.
Sprouting Mossy Fibers In Vitro
Ryuta Koyama, Maki K. Yamada, Shigeyoshi Fujisawa, Ritsuko Katoh-Semba, Norio Matsuki, and Yuji Ikegaya
(see pages 7215-7224)
In patients with temporal lobe epilepsy, mossy fiber (MF) axons of dentate granule cells sprout recurrent branches that meander to the inner molecular layer and form functional excitatory synapses with granule cell dendrites. The resulting excitatory feedback loops are thought to enhance the development of chronic, unprovoked seizures. Several animal models of seizures induce sprouting, suggesting that it is activity-dependent. This week, Koyama et al. examine the role of brain-derived neurotrophic factor (BDNF) in MF sprouting in organotypic slice cultures of hippocampus and entorhinal cortex. They found that activation of l-type calcium channels led to expression and extracellular release of BDNF that then acted via TrkB receptors on granule cells to trigger sprouting. Focal application of BDNF beads in the hilus induced sprouting, but bath application did not, suggesting that the trophic effect is attributable to enhanced axon branching rather than chemoattraction.
The Channel to Direction Selectivity
Ander Ozaita, Jerome Petit-Jacques, Béla Völgyi, Chi Shun Ho, Rolf H. Joho, Stewart A. Bloomfield, and Bernardo Rudy
(see pages 7335-7343)
Directionally selective retinal ganglion cells (RGCs) activate in response to light stimuli in a preferred direction. The prevention of RGC firing in the opposite direction is thought to originate from GABAergic input from starburst amacrine cells. Starburst amacrine cells are unusual in several ways: they apparently lack action potentials, their distal dendrites are larger than proximal segments, and their dendrites can act independently. This week, Ozaita et al. provide evidence that Kv3-type voltage-dependent potassium channels combine with the features of amacrine cells to allow direction selectivity. Kv3 channels usually enhance fast spiking in neurons because they activate quickly and deactivate quickly on repolarization. However, in amacrine cells these channels appear to act as a voltage-dependent shunt. The radial symmetry of the starburst cells, and the shunt provided by a higher proximal dendritic expression of Kv3, provides a mechanism by which single dendrites respond better to light stimuli moving centrifugally rather than centripetally.
Neurobiology of Disease
Understanding Deep Brain Stimulation in Parkinsonism
Izhar Bar-Gad, Shlomo Elias, Eilon Vaadia, and Hagai Bergman
(see pages 7410-7419)
Many successful therapies develop before the underlying mechanisms are understood. Such is the case for the treatment of Parkinsonism with high-frequency “deep brain stimulation” (DBS). Because DBS had similar effects to local ablation, total inhibition of neuronal firing seemed at first to be a likely mechanism. In this week's Journal, Bar-Gad et al. revisit this issue using microstimulation of the globus pallidus (GP) in an MPTP-injected monkey. They simultaneously stimulated and recorded from the GP, and optimized their recording to minimize stimulus artifacts. Their results suggest a complex response of units in the GP to low-frequency and high-frequency stimulation. Low-frequency stimulation often evoked triphasic responses in neurons whereas high-frequency stimulation “locked” neuronal firing to the stimulus in most neurons. Although the authors could not separate segments within the GP, their results clearly indicate that DBS disrupts activity in a manner distinct from ablation, perhaps by effectively “jamming” the abnormal activity characteristic of movement disorders such as Parkinsonism.