1. 0Ketamine Effects Are Mediated by Inhibition of I0h
Xiangdong Chen, Shaofang Shu, and Douglas A. Bayliss
Ketamine is an anesthetic, analgesic, and psychedelic drug that produces slow cortical oscillations reminiscent of those observed in deep sleep. Ketamine inhibits NMDA receptors, but mice lacking an NMDA receptor subunit still exhibit the behavioral effects of ketamine, suggesting the drug may have other targets. Indeed, this week Chen et al. report that the behavioral effects of ketamine are likely to result from inhibition of hyperpolarization-activated cyclic nucleotide-modulated (HCN1) cation channels. These channels mediate Ih, the “sag” current that is activated by action potential after hyperpolarization and helps stabilize membrane potential, regulates spike frequency, and contributes to a dendritic shunt that causes nonlinear summation of EPSPs. In pyramidal neurons in mouse cortical slices, ketamine inhibited Ih, caused a hyperpolarizing shift in resting membrane potential, and enhanced summation of excitatory currents – effects likely to produce cortical oscillations. Importantly, none of these effects, nor hypnotic effects in vivo, were produced in mice lacking HCN1 channels.
2. 0IGF-1 Stimulates Precursor Proliferation
Georges Mairet-Coello, Anna Tury, and Emanuel DiCicco-Bloom
Brain size depends on the number of precursor divisions that occur during development. Whether a cell divides or differentiates is largely determined at the cell cycle transition fromG1 to S phase, so precise regulation of this step is especially important. The transition is mediated by increases in cyclins D and E, their interactions with cyclin-dependent kinases (CDKs), and subsequent phosphorylation of downstream targets; inducing cyclin expression with external factors increases neurogenesis and brain size. Mairet-Coello et al. have found that insulin-like growth factor 1 (IGF-1) is one such factor. Intracerebroventricular injections of IGF-1 into rat embryos increased levels of cyclins D and E while decreasing mRNA levels of CDK inhibitors. These changes resulted in increased DNA synthesis and an increased number of cells in the forebrain at postnatal day 10. Injecting antibodies that neutralize IGF-1 into mouse embryos reduced DNA synthesis, suggesting IGF-1 regulates cell proliferation during normal development.
3. Selectivity in Cued Saccade Sequences
Tamara K. Berdyyeva and Carl R. Olson
Complex motor tasks often consist of multiple simple actions performed in a specific sequence. Proper sequencing of simple actions has been suggested to depend on neurons that fire preferentially during specific steps in a sequence. Candidate ordinal position neurons are present in several motor areas, including the supplementary eye fields (SEF). According to Berddyeva and Olson, neurons in SEF respond not only during specific steps in a predefined, learned sequence of saccades (as has been shown previously), but also during the equivalent step in a sequence of saccades that were cued by a learned sequence of visual stimuli and could not be planned in advance. Although many of these neurons also fired preferentially when a reward of a specific size was expected, and many neurons exhibited increased or decreased firing over the course of a trial, neither reward anticipation nor passage of time was sufficient to explain the differential firing during the sequence tasks.
4. 0Synaptic Release Probability Is Reduced in SMA
Lingling Kong, Xueyong Wang, Dong W. Choe, Michelle Polley, Barrington G. Burnett, Marta Bosch-Marcé, John W. Griffin, Mark M. Rich, and Charlotte J. Sumner
Spinal muscular atrophy (SMA) is a motor neuron disease that causes severe, sometimes lethal, muscle weakness. SMA is caused by defects in the gene survival motor neuron 1 (SMN1), but how these defects lead to muscle atrophy are unknown. Kong et al. have begun to address this question using SMN1-mutant mice. Unlike mutations that cause other motor neuron diseases, SMN mutations caused minimal motor neuron degeneration and denervation. The amplitude of endplate potentials was decreased in mutant mice, however, and this appeared to stem from a decrease in the probability of vesicle release. Molecular and morphological maturation of the postsynaptic components of neuromuscular junctions were delayed in mutant mice, as was maturation (and resultant strengthening) of the contractile apparatus in myofibers. Although maturation of neuromuscular junctions and myofibers depends on synaptic inputs from motor neurons, the precise sequence of cause and effect in SMA remains to be determined.