This Week in The Journal
New Isozyme-Specific Sensors Elucidate a Novel PKC Isozyme
Lesley A. Colgan, Paula Parra-Bueno, Heather L. Holman, Xun Tu, Anant Jain, et al.
(see pages 5432–5447)
In our day-to-day lives, we are constantly taking in new information and learning new things. This ability relies on dynamic activity-dependent changes in strength at synapses between dendritic spines and axons through which neurons communicate to each other. These synaptic changes, or plasticity, occur due to coordinated biochemical reactions that are stabilized by later alterations in genetic transcription in the nuclei of cells. While the role of the protein kinase C (PKC) family in this process has been well described, many PKC subfamilies, or isozymes, remain unidentified and are thus unexplored. In this issue, Colgan et al. developed new isozyme-specific sensors to discover novel PKC isozymes in hippocampal CA1 pyramidal neurons of mice. They found that molecular signaling through PKCδ plays an intricate role in plasticity, a role that is dependent upon the timing and location of its activation. In their study, they discovered that plasticity driven by stimulating a single CA1 dendritic spine required rapid PKCδ activation that returned to normal following only 5 min. But when multiple spines were stimulated, PKCδ activation was far more widespread and long lasting. This robust PKCδ activation facilitated synaptic plasticity by regulating the activity of transcription factors that enable the coupling of spine plasticity to nucleic gene transcription. The authors herein overcome current limitations in studying the discrete, complex roles that PKC isozymes play in synaptic plasticity with novel tools that will surely enable further investigation to broaden our understanding of the cellular basis of learning and memory as well as disease states in which learning and memory go awry.
Representative lifetime images of isozyme-specific docking of C-kinase substrate sensor for isozyme δ (IDOCKSδ) in the primary dendrite in response to 1 or 5 spine stimulation. Warmer colors indicate decreased lifetime and activation of PKCδ. Scale bar, 2 µm.
Retrotrapezoid Nucleus Neurons as Mediators of the Drive to Breathe
George M.P.R. Souza, Daniel S. Stornetta, Yingtang Shi, Eunu Lim, Faye E. Berry, et al.
(see pages 5501–5520)
While breathing may seem thoughtless and natural, it is in fact a highly coordinated motor activity dependent upon optimal blood gas homeostasis. Respiratory chemoreceptors stimulate motor neurons to effectively regulate arterial carbon dioxide (CO2) and oxygen levels and to enable lung ventilation. Several motor neuron types are implicated as central respiratory chemoreceptors, yet the mechanisms underlying respiratory homeostasis remain highly disputed. While evidence supports that neuromedin-B (Nmb)-expressing retrotrapezoid nucleus (RTN) neurons are critical regulators of the CO2-dependent ventilatory response, key gaps in knowledge remain. In this issue, Souza et al. provide the first ever functional evidence for RTN neurons as mediators of the CO2-dependent drive to breathe in mice. They created a novel transgenic line of mice enabling ablation of RTN neurons expressing Nmb. They found that in the absence of these neurons, mice experienced severe respiratory deficits; they had respiratory acidosis due to alveolar hypoventilation (high CO2 levels due to slowed breathing) and their profoundly unstable breathing resulted in significant sleep disruptions. Following neuron ablation, oxygen-sensitive mechanisms were increased substantially, suggesting that a compensatory peripheral chemoreceptor-mediated mechanism was triggered due to CO2 imbalance caused by RTN neuron deletion. These data demonstrate that deficits in Nmb-expressing RTN neuron functioning may underlie abnormal breathing conditions that contribute to sleep disorders. Beyond that, the transgenic mouse line developed by Souza et al. is notable: it could be leveraged as a powerful tool in the development of treatments for abnormal respiratory homeostasis and respiratory-related sleep deficits.
