Oxytocin Regulates Three Currents in CA2 Neurons
Jing-Jing Liu, Katherine W. Eyring, Gabriele M. König, Evi Kostenis, and Richard W. Tsien
(see pages 7707–7720)
Interest in hippocampal area CA2 has grown substantially since the area was discovered to have essential roles in social interaction. In particular, blocking output from dorsal CA2 to ventral hippocampus impairs social recognition memory, as does knocking out oxytocin receptors in CA2. Oxytocin—a hypothalamic hormone that regulates social behaviors and emotions—increases the excitability of CA2 pyramidal cells and induces burst firing. To identify the molecular mechanisms through which oxytocin exerts these effects, Liu et al. recorded from oxytocin-receptor-expressing CA2 pyramidal neurons in hippocampal slices treated with various ion-channel blockers.
Consistent with previous work, an oxytocin agonist depolarized CA2 neurons, increased membrane resistance, and induced burst firing. It also lowered the spike threshold. Measurement of currents activated at different membrane voltages indicated that agonist-induced depolarization resulted from inhibition of an inwardly rectifying potassium current (IKir). Unexpectedly, oxytocin also reduced Ih, an inward (depolarizing) current carried by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels. Closing these channels is expected to slow the depolarization resulting from IKir inhibition, but it also increases membrane resistance, thus increasing the impact of excitatory synaptic input. Consistent with this, the oxytocin agonist increased the amplitude of spontaneous EPSCs in pyramidal neurons. Finally, the oxytocin agonist enhanced a tetrodotoxin-resistant persistent sodium current that produced subthreshold membrane oscillations; notably, this current had not previously been reported in the hippocampus.
These results suggest that oxytocin exerts its effects in CA2 pyramidal cells by modulating three currents: it inhibits Kir channels, leading to membrane depolarization; it inhibits HCN channels, slowing the depolarization and increasing resistance, thus potentiating the effects of excitatory input; and it potentiates a tetrodotoxin-resistant persistent sodium current that contributes to subthreshold membrane oscillations and thus promotes burst firing. Together, these effects may enhance synaptic plasticity underlying social recognition memory.
Cortical neurons normally develop complex arbors in culture (top), but dendrites of neurons lacking PINK1 form fewer branches. See Otero et al. for details.
PINK1 Promotes Growth of Dendritic Branches and Spines
P. Anthony Otero, Gabriella Fricklas, Aparna Nigam, Britney N. Lizama, Zachary P. Wills, et al.
(see pages 7848–7860)
Homozygous mutation of the kinase PINK1 causes Parkinson's disease, and heterozygous mutation is associated with cognitive impairment. Neurodegeneration resulting from loss of PINK1 function is thought to stem from impaired removal of damaged mitochondria via mitophagy. PINK1 is normally targeted to mitochondria, and, if themitochondrion is damaged, PINK1 recruits the ubiquitin ligase Parkin, another protein mutated in Parkinson's disease. Parkin tags damaged mitochondria for lysosomal degradation. In healthy mitochondria, however, PINK1 is cleaved, and the fragment containing the kinase domain is exported to the cytoplasm, where it phosphorylates additional targets. One consequence of this is enhanced activation of protein kinase A (PKA) and secretion of brain-derived neurotrophic factor. PINK1 also promotes neuron differentiation and synaptic plasticity. Otero et al. now provide evidence that loss of PINK1 also reduces dendritic arborization and spine density.
The total number of dendritic branches and the length of distal branches were lower in cortical neurons cultured from PINK1-deficient mice than those from wild-type mice. Moreover, the density of thin, stubby, and mushroom-shaped dendritic spines was lower in PINK1-deficient neurons than in controls. Consequently, the frequency of miniature EPSCs was lower than normal in PINK1-deficient neurons. All of these effects were reversed by expressing human PINK1 in neurons from mutant mice, suggesting human and mouse PINK1 have similar roles in the growth of dendritic branches and spines.
Previous work showed that by promoting activation of PKA, PINK1 promotes phosphorylation of p47, a protein that contributes to spine formation by regulating local protein synthesis. Consistent with this, PINK1 knockout reduced p47 phosphorylation in the brain. Notably, expressing a mutated form of p47 that mimics the phosphorylated protein rescued dendritic branching and partially rescued spine density in PINK1-deficient cortical neurons. A nonphosphorylatable form of p47 partially rescued dendritic branching, but only of proximal dendrites.
These results suggest that PINK1 promotes dendritic branching and spine formation and maturation partly by promoting PKA-dependent phosphorylation of p47 and partly through other mechanisms. The loss of dendritic branches and spines may contribute to cognitive deficits in people with PINK1 mutations. Thus, the data add to growing evidence that the consequences of PINK1 deficiency extend beyond impaired mitophagy.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
