Action Potential Shaping by Stimulus History
Gonzalo G. de Polavieja, Annette Harsch, Ingo Kleppe, Hugh P. C. Robinson, and Mikko Juusola
(see pages 5657-5665)
In usual parlance, “action potential” is synonymous with all-or-none, with each event a uniform shape. In this view, the large, but brief, membrane conductance change associated with an action potential momentarily shunts incoming synaptic charge and thus “resets” the membrane, as depicted in simple “integrate and fire” neuronal models. However, as de Polavieja et al. show this week, the conductance change associated with synaptic inputs also can influence the action potential waveform. The authors made whole-cell recordings from rat cortex pyramidal neurons in “dynamic clamp” mode, in which they drove action potentials with conductance transients that mimicked natural synaptic input. Following a stimulus pattern similar to naturally occurring synaptic inputs, the action potential waveform reflected the stimulation in the preceding 50 ms. Thus the action potential waveform encodes information about the stimulus history at the single-cell level. This effect will be most pronounced for slow synaptic conductances lasting tens or hundreds of milliseconds.
Bax and Sexually Dimorphic Motoneuron Death
Dena A. Jacob, C. Lynn Bengston, and Nancy G. Forger
(see pages 5638-5644)
The spinal nucleus of the bulbocavernosus (SNB) in the lumbar spinal cord provides a unique opportunity to examine target-dependent cell death. Motoneurons in the SNB undergo sexually dimorphic and target-dependent cell death. Both the motoneurons and their target muscles degenerate in female rodents around the time of birth, but they can be rescued with androgen treatment. Androgens are thought to act on the muscle, leading to release of trophic factors necessary for motoneuron survival. Interestingly, SNB motoneurons are spared in amyotrophic lateral sclerosis. Jacob et al. tested the role of Bcl family proteins in SNB motoneurons by examining female mice lacking the pro-death Bax gene. SNB neurons survived in Bax-/- mice, virtually eliminating the sexual dimorphism. The number of target muscle fibers in Bax-/- females was somewhat increased, but still 50-fold less than in males. Thus Bax is necessary for SNB motoneuron death, but not for the sexual differentiation of the target muscles.
Endogenous Cannabinoids and Reward in Monkeys
Zuzana Justinova, Marcello Solinas, Gianluigi Tanda, Godfrey H. Redhi, and Steven R. Goldberg
(see pages 5645-5650)
The rewarding effects of exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) have been well studied inside and outside the laboratory. Although the endogenous cannabinoid anandamide is less potent than THC, it also acts at CB1 receptors. It has been more difficult to establish whether endocannabinoids are actually involved in normal brain reward pathways. In this week's Journal, Justinova et al. tested whether squirrel monkeys would self-administer anandamide. This endocannabinoid has a short half-life because of rapid reuptake by membrane transporters and subsequent intracellular breakdown by fatty acid amide hydrolase. The authors also tested the stable synthetic analog methanandamide. Monkeys rapidly learned to press a lever to self-administer intravenous anandamide or methanandamide with a pattern similar to cocaine. When CB1 receptors were blocked, lever-pressing behavior declined for anandamide and methanandamide, but not cocaine. The agonist properties of anandamide enable only quite brief reinforcing effects; however, drugs that affect its release or metabolism could have potential for abuse.
Neurobiology of Disease
Loss of NF1 and Regulation of Neural Stem Cells
Biplab Dasgupta and David H. Gutmann
(see pages 5584-5594)
Mutations in the NF1 gene in neurofibromatosis type 1 lead to tumor formation in the peripheral nervous system and CNS arising from Schwann cells and astroglial cells, respectively. Mice that lack NF1 show a similar phenotype. This suggests that the gene product, neurofibromin, is involved in growth control. Loss of NF1 can activate Ras signaling and lead to proliferation of tumor cells. The tumors also can contain groups of nestin-positive cells, suggesting possible dysregulation of neural stem cells (NSCs). This week, Dasgupta and Gutmann examined the effect of neurofibromin on NSC proliferation. In Nf1-/- and Nf1-/+ mice, the authors found increased NSC proliferation and self-renewal in vitro and increased astrocyte precursors with immature morphology. This effect was rescued by expression of the Ras-GTPase activating protein (GAP) protein domain in neurofibromin. Haploinsufficiency (Nf1+/-), as can occur in neurofibromatosis patients, produced intermediate effects on NSC growth control.