Cellular/Molecular
Synaptic Vesicle Generation Varies Across Regions
Karen Newell-Litwa, Sreenivasulu Chintala, Susan Jenkins, Jean-Francois Pare, LeeAnne McGaha, Yoland Smith, and Victor Faundez
(see pages 820–831)
Synaptic vesicle recycling maintains the pool of vesicles available to release neurotransmitter upon stimulation. Vesicles are recycled through several routes, including rapid refilling and slower processes involving endocytosis. Sometimes, particularly after prolonged stimulation, endocytic vesicles fuse into larger endosomes from which synaptic vesicles subsequently bud. Genesis of synaptic vesicles by this pathway requires adaptor protein complex-3 (AP-3), which, like other APs, helps to determine vesicular cargo. Vesicle-recycling pathways have generally been assumed to be similar across neurons, but Newell-Litwa et al. report that loss of AP-3 in mice had different effects in different brain regions. Although AP-3 was similarly abundant in striatum and dentate gyrus, after AP-3 knock-out, synaptic vesicle size increased in dentate but decreased in striatum. Disruption of a complex that interacts with AP-3, Biogenesis of Lysosome-Related Organelles Complex-1 (BLOC-1), decreased levels of AP-3 and its cargo in presynaptic compartments in dentate but not in striatum. Therefore, vesicle biogenesis pathways likely vary across regions.
Development/Plasticity/Repair
Stimulation Pattern Determines Synaptic Effects
Malgorzata Jasinska, Ewa Siucinska, Anita Cybulska-Klosowicz, Elzbieta Pyza, David N. Furness, Malgorzata Kossut, and Stanislaw Glazewski
(see pages 1176–1184)
Learning is thought to depend on changes in synaptic strength and number and in the number and shape of dendritic spines. To quantify changes produced by repeatedly stimulating a single whisker and shocking the tail of mice, Jasinska et al. counted asymmetric (likely excitatory) and symmetric (likely inhibitory) synapses on dendritic spines and shafts in barrel cortex. Interestingly, the stimuli induced different changes depending on the presentation pattern. When whisker stimulation and tail shock were uncorrelated, the density of dendritic spines and asymmetric synapses increased in the affected barrel. In contrast, when whisker stimulation and tail shock were paired to produce classical conditioning, the density of symmetric synapses on spines increased, but the densities of spines and asymmetric synapses were unchanged. This produced a larger number of spines with both an inhibitory and an excitatory synapse. In addition, the paired stimulation increased presynaptic GABA concentrations at symmetric synapses.
Behavioral/Systems/Cognitive
5-HT2C Receptors in Orbitofrontal Cortex Regulate Perseverance
Vasileios Boulougouris and Trevor W. Robbins
(see pages 930–938)
Sometimes persistence is beneficial, but when a behavior ceases to produce rewards, it is usually better to try a new strategy. Such behavioral flexibility is thought to be regulated by inhibitory orbitofrontal projections to the caudate nucleus. Descending control is modulated by ascending monoaminergic projections, whose activity varies with motivation, stress, etc. Improper functioning of monoaminergic systems and resulting dysregulation of descending control might therefore contribute to compulsive behaviors. To study behavioral inflexibility in rats, researchers use a reversal learning task in which pressing one lever stops yielding reward and the animals must instead press a different lever. After systemic administration of 5-HT2C receptor antagonists, rats switch strategies more quickly, whereas 5-HT2A receptor antagonists prolong pressing of the unrewarded lever. By injecting antagonists directly into different brain regions, Boulougouris and Robbins have now found that 5-HT2C receptor antagonists act in the orbitofrontal cortex. The site of action of 5-HT2A receptor antagonists, however, remains unknown.
Neurobiology of Disease
Rapamycin Protects Neurons from Toxins
Cristina Malagelada, Zong Hao Jin, Vernice Jackson-Lewis, Serge Przedborski, and Lloyd A. Greene
(see pages 1166–1175)
Cell proliferation, growth, degeneration, and death are controlled by a complex network of signaling molecules that includes multiple positive- and negative-feedback loops. A major hub in this network is the mammalian target of rapamycin (mTOR), a kinase that, through multiple pathways, regulates cell metabolism in response to growth factors, nutrients, and cellular stressors. Growth factors activate mTOR via the prosurvival kinase Akt, and mTOR further activates Akt. In contrast, cellular stressors and toxins linked to Parkinson's disease suppress mTOR activation via RTP801. By suppressing mTOR activity, RTP801 reduces activation of Akt and thus causes neuronal apoptosis. Malagelada et al. report that induction of RTP801 in response to toxins requires mTOR activity. Moreover, rapamycin, a drug that inhibits some actions of mTOR, prevented toxin-induced increases in RTP801 translation, but spared mTOR-mediated activation of Akt in neuronal cultures. Furthermore, rapamycin injections reduced toxin-induced neuronal death in the substantia nigra of mice.