Prostaglandins Link Pyramidal Cell Activity to Vasodilation
Clotilde Lecrux, Xavier Toussay, Ara Kocharyan, Priscilla Fernandes, Sujay Neupane, et al.
(see pages 9836–9847)
Restoring resting ion distributions following action potentials and synaptic activity consumes much energy. Neurovascular coupling produces hyperemia—increased blood flow to active brain areas—ensuring sufficient delivery of glucose and oxygen to restore energy balance. Although numerous molecules generated by neurons and astrocytes have been implicated in functional hyperemia, whether these act serially or in parallel in vivo is unclear. Therefore, Lecrux et al. examined neuronal activation by whisker deflection and the effect of various inhibitors on hyperemia in rat cortical barrels. Stimulation activated a subset of pyramidal neurons, including some that expressed cyclooxygenase-2 (COX-2), which produces the vasodilator prostaglandin E2. Inhibiting COX-2 and NMDA receptors (NMDARs) nonadditively reduced hyperemic responses, suggesting NMDAR activity stimulates prostaglandin production. A subset of GABAergic neurons were also activated by whisker deflection, and GABAA receptors contributed to hyperemic responses independently of NMDARs. Although astrocytic synthesis of vasodilating epoxyeicosatrienoic acids contributed to functional hyperemia, this apparently occurred downstream of neuronal activation.
DNA Breaks Are Likely to Cause Apoptosis in SVZ Cells
Susanne A. Gatz, Limei Ju, Ralph Gruber, Eva Hoffmann, Antony M. Carr, et al.
(see pages 10088–10100)
Replication errors, reactive oxygen species, and ionizing radiation (IR) regularly cause double-strand breaks (DSBs) in DNA, which can cause chromosomal rearrangement, disruption of transcriptional regulation, and cell death. To minimize these consequences, proteins that bind DSBs initiate processes leading to cell-cycle arrest and DNA repair or to apoptosis. Gatz et al. show that during CNS development, proliferating cells in the subventricular zone (SVZ) are more susceptible to IR-induced apoptosis than postmitotic cells in the intermediate zone (IZ) or mature neurons. Although cell-cycle arrest and DNA repair occurred in embryonic SVZ, fewer DSBs were required to initiate apoptosis at this stage. Furthermore, the DSB threshold for cell-cycle arrest was relatively high, allowing surviving cells to proceed to the IZ before DSBs were repaired. Normally, DNA ligase IV (LIG4) repairs DSBs in IZ, but reduction of LIG4 activity, which results from a human mutation, slows DSB repair, thus causing increased susceptibility to IR-induced apoptosis in the IZ.
Increasing Optical Quality Does Not Improve Stereopsis
Björn N.S. Vlaskamp, Geunyoung Yoon, and Martin S. Banks
(see pages 9814–9818)
The eyes create two-dimensional images of the three-dimensional world. Because the two eyes have slightly different views of the world, objects that are nearer or farther away than the fixation point are imaged at different relative positions in the two eyes. The brain reconstructs a representation of the three-dimensional world largely using this disparity between the two retinal images, and disparities smaller than a photoreceptor can be perceived as a difference depth. Because previous studies showed that reducing optical quality decreases stereo resolution, Vlaskamp et al. asked whether improving optical quality can improve stereopsis. They reduced optical blur by reducing chromatic aberration and reducing the effective pupil size. Although this treatment improved acuity and contrast sensitivity, it had no effect on stereo resolution, even under conditions of low contrast. The authors conclude that stereo resolution is limited by small eye movements that occur during fixation, and this limit cannot be overcome by supernormal optics.
Neurobiology of Disease
Reducing α-Synuclein Expression Reverses Pathology
Youngshin Lim, Victoria M. Kehm, Edward B. Lee, James H. Soper, Chi Li, et al.
(see pages 10076–10087)
α-Synuclein is normally associated with synaptic vesicles in presynaptic terminals. Although its function is unclear, roles in folding of SNARE proteins, vesicle clustering, and plasticity have been proposed. Several neurodegenerative diseases, including Parkinson's disease (PD), are characterized by intracellular inclusions of misfolded, aggregated, and phosphorylated α-synuclein. Whether α-synuclein, its phosphorylation, or the inclusions cause degeneration is unknown, however. To investigate this, Lim et al. conditionally expressed a human PD-linked form of α-synuclein in mice. α-Synuclein began to accumulate in limbic areas at 4 months and neurodegeneration was prominent by 20 months. Levels of synaptic vesicle proteins were reduced by 8 months, and impairment of hippocampal-dependent contextual fear conditioning was correlated with the degree of α-synuclein accumulation at this time. Suppressing transgene expression starting at 9 months, however, reversed hippocampal α-synuclein accumulations, loss of presynaptic proteins, and memory impairments, indicating that α-synuclein clearance might be beneficial in the treatment of PD and other synucleinopathies.