Cellular/Molecular
CDK5 and Calcineurin Regulate Synaptic Ca2+ Influx
Sung Hyun Kim and Timothy A. Ryan
(see pages 8937–8950)
The cyclin-dependent kinase CDK5 has numerous targets and helps regulate nearly every aspect of neuron development and function, including migration, neurite outgrowth, synaptic vesicle release and recycling, synaptic plasticity, and neuron death. At synaptic terminals, CDK5 and the Ca2+-dependent phosphatase calcineurin work in opposition to regulate the distribution of synaptic vesicles between resting and recycling pools, thus regulating release during sustained activity. Kim and Ryan report that these molecules also regulate release probability in response to single action potentials by modulating influx through N-type voltage gated Ca2+ channels (CaV2.2) in rat hippocampal neurons. Specifically, knocking down the α isoform of calcineurin subunit A (CANα) reduced, whereas knocking down CDK5 increased Ca2+ influx and exocytosis evoked by single spikes. Blocking CaV2.2 occluded the effects of CDK5 knockdown, but blocking P/Q-type channels, which also contribute to synaptic vesicle release, did not. Additional experiments suggested that the relative activity of CDK5 and CNAα varied across synapses, producing differences in spike-induced Ca2+ influx.
Development/Plasticity/Repair
Sema4D Induces GABAergic Synapse Formation
Marissa S. Kuzirian, Anna R. Moore, Emily K. Staudenmaier, Roland H. Friedel, and Suzanne Paradis
(see pages 8961–8973)
Semaphorin proteins help guide axon growth and direct synaptogenesis during CNS development, and semaphorin-dependent signaling is required for dendritic development and formation of postsynaptic structures. Knockdown of Sema4D reduces the number of GABAergic synapses formed onto rat hippocampal neurons, and Kuzirian et al. have discovered that Sema4D also induces synapse formation on these neurons. Within 30 min, Sema4D treatment increased the density of puncta of apposed presynaptic and postsynaptic components of GABAergic synapses. In neurons expressing fluorescently labeled gephyrin, a postsynaptic scaffolding protein required for GABAergic synapse assembly, time-lapse imaging revealed that rapid increases in the number of postsynaptic puncta resulted primarily from splitting of pre-existing puncta. The Sema4D receptor PlexinB1 was required for these effects. The frequency of miniature IPSCs increased within 2 h of Sema4D treatment, suggesting that newly formed synapses later became functional. Finally, in hippocampal slice cultures in which epileptiform excitatory network activity had been induced, Sema4B increased inhibition and reduced excitation, thereby reducing spontaneous activity.
Behavioral/Cognitive
Male Stress Alters Stress Response in Offspring
Ali B. Rodgers, Christopher P. Morgan, Stefanie L. Bronson, Sonia Revello, and Tracy L. Bale
(see pages 9003–9012)
Much evidence indicates that maternal stress during pregnancy affects fetal brain development and predisposes offspring to cognitive deficits and neuropsychiatric disorders. Although epidemiological studies have suggested that paternal stress also predisposes offspring to neuropsychiatric disease, much less is known about this phenomenon. Therefore, Rodgers et al. subjected male mice to various stressors for 6 weeks before the mice mated. The offspring of stressed mice showed smaller increases in corticosterone levels after acute restraint stress than controls, and the global pattern of gene expression was altered in stress-regulating brain regions in the offspring of stressed males. Notably, genes regulated by glucocorticoid receptors, histone acetyltransferases, and microRNAs were enriched in these areas. Despite these changes, however, offspring of stressed males did not differ from controls on behavioral responses to stressful conditions. The molecular effects of paternal stress were probably mediated by epigenetic changes during spermatogenesis. Indeed, nine microRNAs were present at higher levels in the sperm of stressed mice than in that of controls.
Neurobiology of Disease
SIRT1 Activator Prevents Neurodegeneration in Mice
Johannes Gräff, Martin Kahn, Alireza Samiei, Jun Gao, Kristie T. Ota, et al.
(see pages 8951–8960)
Caloric restriction and intermittent fasting have been shown to increase lifespan, enhance synaptic plasticity and adult neurogenesis, and slow neurodegeneration in several disease models. The effects of caloric restriction are thought to be partly mediated by upregulation of sirtuins, particularly SIRT1, a protein deacetylase that upregulates proteins involved in energy metabolism, stress responses, and cell survival. Gräff et al. found that restricting food intake (providing mice with only 70% of the food normally consumed during ad libitum access) prevented neurological effects of conditionally expressing the CDK5 activator p25 in forebrain neurons. Specifically, 6 weeks of p25 expression causes neurodegeneration and reduces synaptic density in the hippocampus, produces deficits in hippocampal long-term potentiation, and impairs memory in object-recognition and fear-conditioning tasks; all of these effects were prevented by restricting caloric intake for 6 weeks before and during p25 expression. More importantly, the same protective effects were produced by giving mice an orally administered, specific SIRT1-activating compound, indicating beneficial effects can be achieved without severe caloric restriction.