Tag Archive for: neurobiology

caspase molecule

Caspases may link brain cell degeneration and cardiac surgery

caspase molecule

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

A review article in the journal Cell Press: Trends in Neuroscience outlines the wide variety of cellular signaling roles for caspase proteins — a type of cellular enzyme best known for its documented role in the natural process of cell death (apoptosis). The authors, including Nemanja Saric, Ph.D., Kazue Hashimoto-Torii, Ph.D., and Nobuyuki Ishibashi, M.D., all from Children’s National Research Institute, pay particular attention to what the scientific literature shows about caspases’ non-apoptotic roles in the neurons specifically. They also highlight research showing how, when activated during a cardiac surgery with anesthesia and cardiopulmonary bypass, these enzymes may contribute to the degeneration of brain cells seen in young children who undergo heart surgery for critical congenital heart defects (CHDs).

Why it matters

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

The authors propose that these non-apoptotic activities of caspases may be behind some of the adverse effects on the developing brain related to cardiac surgery and anesthesia. Those adverse effects are known to increase risk of behavioral impairments in children with congenital heart disease who underwent cardiac surgery with both anesthesia and cardiopulmonary bypass at a very young age.

This work is the first to propose a possible link between developmental anesthesia neurotoxicity and caspase-dependent cellular responses.

The patient benefit

Better understanding of the time and dose-dependent effects of general anesthetics on the developing brain, particularly in children who have genetic predispositions to conditions such as CHDs, will help researchers understand their role (if any) in behavioral problems often encountered by these patients after surgery.

If found to be a contributing factor, perhaps new therapies to mitigate this caspase activity might be explored to alleviate some of these adverse effects on the developing brain.

What’s next?

The authors hope to stimulate more in-depth research into caspase signaling events, particularly related to how these signaling events change when an anesthetic is introduced. Deeper understanding of how anesthetics impact caspase activation in the developing brain will allow for better assessments of the risk for children who need major surgery early in life.

Children’s National leads the way

Children’s National Hospital leads studies funded by the U.S. Department of Defense to better understand how these other roles of caspases, which until now have not been well-documented, may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.

Vittorio Gallo

Special issue of “Neurochemical Research” honors Vittorio Gallo, Ph.D.

Vittorio Gallo

Investigators from around the world penned manuscripts that were assembled in a special issue of “Neurochemical Research” that honors Vittorio Gallo, Ph.D., for his leadership in the field of neural development and regeneration.

At a pivotal moment early in his career, Vittorio Gallo, Ph.D., was accepted to work with Professor Giulio Levi at the Institute for Cell Biology in Rome, a position that leveraged courses Gallo had taken in neurobiology and neurochemistry, and allowed him to work in the top research institute in Italy directed by the Nobel laureate, Professor Rita Levi-Montalcini.

For four years as a student and later as Levi’s collaborator, Gallo focused on amino acid neurotransmitters in the brain and mechanisms of glutamate and GABA release from nerve terminals. Those early years cemented a research focus on glutamate neurotransmission that would lead to a number of pivotal publications and research collaborations that have spanned decades.

Now, investigators from around the world who have worked most closely with Gallo penned tributes in the form of manuscripts that were assembled in a special issue of “Neurochemical Research” that honors Gallo “for his contributions to our understanding of glutamatergic and GABAergic transmission during brain development and to his leadership in the field of neural development and regeneration,” writes guest editor Arne Schousboe, of the University of Copenhagen in Denmark.

Dr. Gallo as a grad student

Vittorio Gallo, Ph.D. as a 21-year-old mustachioed graduate student.

“In spite of news headlines about competition in research and many of the negative things we hear about the research world, this shows that research is also able to create a community around us,” says Gallo, chief research officer at Children’s National Hospital and scientific director for the Children’s National Research Institute.

As just one example, he first met Schousboe 44 years ago when Gallo was a 21-year-old mustachioed graduate student.

“Research can really create a sense of community that we carry on from the time we are in training, nurture as we meet our colleagues at periodic conferences, and continue up to the present. Creating community is bi-directional: influencing people and being influenced by people. People were willing to contribute these 17 articles because they value me,” Gallo says. “This is a lot of work for the editor and the people who prepared papers for this special issue.”

In addition to Gallo publishing more than 140 peer-reviewed papers, 30 review articles and book chapters, Schousboe notes a number of Gallo’s accomplishments, including:

  • He helped to develop the cerebellar granule cell cultures as a model system to study how electrical activity and voltage-dependent calcium channels modulate granule neuron development and glutamate release.
  • He developed a biochemical/neuropharmacological assay to monitor the effects of GABA receptor modulators on the activity of GABA chloride channels in living neurons.
  • He and Maria Usowicz used patch-clamp recording and single channel analysis to demonstrate for the first time that astrocytes express glutamate-activated channels that display functional properties similar to neuronal counterparts.
  • He characterized one of the spliced isoforms of the AMPA receptor subunit gene Gria4 and demonstrated that this isoform was highly expressed in the cerebellum.
  • He and his Children’s National colleagues demonstrated that glutamate and GABA regulate oligodendrocyte progenitor cell proliferation and differentiation.
Purkinje cells

Purkinje cells are large neurons located in the cerebellum that are elaborately branched like interlocking tree limbs and represent the only source of output for the entire cerebellar cortex.

Even the image selected to grace the special issue’s cover continues the theme of continuity and leaving behind a legacy. That image of Purkinje cells was created by a young scientist who works in Gallo’s lab, Aaron Sathyanesan, Ph.D. Gallo began his career working on the cerebellum – a region of the brain important for motor control – and now studies with a team of scientists and clinician-scientists Purkinje cells’ role in locomotor adaptive behavior and how that is disrupted after neonatal brain injury.

“These cells are the main players in cerebellar circuitry,” Gallo says. “It’s a meaningful image because goes back to my roots as a graduate student and is also an image that someone produced in my lab early in his career. It’s very meaningful to me that Aaron agreed to provide this image for the cover of the special issue.”