Special Brain Cell Helps New Neurons Survive

A specialized type of brain cell that down-regulates stem cell activity seems to encourage the survival of stem cell progeny, according to new research from the laboratory of Hongjun Song, professor of neurology and director of Johns Hopkins Medicine’s Institute for Cell Engineering’s Stem Cell Program.

Uncovering the precise mechanism by which these cells regulate the life and death of neurons is a central to understanding neurodegenerative diseases, aging, and Alzheimer’s disease, since the activity of these cells is linked to these conditions.

“We’ve identified a critical mechanism for keeping newborn neurons alive,” said Song.  “Not only can this help us understand the underlying causes of some diseases, it may also be a step toward overcoming barriers to therapeutic cell transplantation.”

Song collaborated with Guo-li Ming and the members of his research group. Ming is a professor of neurology at the Institute for Cell Engineering.  Song’s team first reported last year that special brain cells called “parvalbumin-expressing interneurons” signal to nearby stem cells not to divide.  They means by which the parvalbumin-expressing interneurons (PEIs) signal to nearby stem cells is by releasing a neurotransmitter called “gamma-aminobutyric acid” (GABA).  In this present study, Ming and Song examined how GABA from surrounding PEIs affects nearby neurons produced by stem cells.

arvalbumin-expressing interneurons
parvalbumin-expressing interneurons

Many of these newborn neurons naturally die soon after they are born.  According to Song, if the new cells survive, these neurons will migrate to a permanent home in the brain and forge connections called synapses with other cells.

To determine whether GABA is a factor in the survival of newborn neurons and their behavior, Song’s team tagged neurons in mouse brains with a fluorescent protein and watched their response to GABA.

“We didn’t expect these immature neurons to form synapses, so we were surprised to see that they had built synapses from surrounding interneurons and that GABA was getting to them that way,” Song said.

In an earlier study, this research team had found that GABA was getting to the synapse-less stem cells by a less direct route – it was drifting across the spaces between cells.

To confirm the finding, the team engineered the interneurons to be stimulated or suppressed by light.  When stimulated by light, the cells activated nearby neurons.  Then they used this light stimulation procedure in live mice, they found that when the specialized neurons were stimulated and gave off more GABA, the newborn neurons survived in greater numbers than otherwise.  This was the opposite of the response of the neural stem cells, which become dormant when given GABA.

Song interpreted these data in the following manner: “This appears to be a very efficient system for tuning the brain’s response to its environment.  When you have a high level of brain activity, you need more newborn neurons, and when you don’t have high activity, you don’t need newborn neurons, but you need to prepare yourself by keeping the stem cells active.  It’s all regulated by the same signal.”

According to Song, the PEIs behave abnormally in neurodegenerative diseases such as Alzheimer’s disease and mental illnesses such as schizophrenia.

“Now we want to see what the role of these interneurons is in the newborn neurons’ next steps” migrating to the right place and integrating into the existing circuitry.  That may be the key to their role in disease,” said Song.  His team is also interested in using the GABA signal to keep transplanted cells alive without affecting other brain processes as a side effect.

See Song J, Sun J, Moss J, Wen Z, Sun GJ, Hsu D, Zhong C, Davoudi H, Christian KM, Toni N, Ming GL, Song H. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat Neurosci. 2013 Dec;16(12):1728-30. doi: 10.1038/nn.3572. Epub 2013 Nov 10.

A Model System for A Devastating Childhood Disease

A Japanese research team from Fukuoka, Japan, specifically from the Department of Pediatrics at the University of Fukuoka, Japan, have used induced pluripotent stem cell technology to make neurons from human patients who suffer from a rare, devastating condition known as Dravet syndrome as a model system.

Dravet syndrome (DS) causes difficult to control seizures within the first year or two of life and later causes cognitive deficits and autistic traits. Dravet’s syndrome is caused by genetic alterations in the SCN1A gene, which encodes the α-subunit of the voltage-gated sodium channel.

DS is very rare – 1/30,000 children, but the mutation is typically not inherited from either parent, but occurs spontaneously in the baby’s cells during development. The best model systems to date are genetically engineered mice, but the differences between human and mouse brains limits the usefulness of this model system.

To make a better model system, workers from the laboratory of Shinichi Hirose took skin biopsy samples from a DS patient, and converted those skin cells into induced pluripotent stem cells (iPSCs), which were then differentiated into neurons. In particular, the neurons that malfunction in DS patients are GABAminergic neurons, and by differentiating DS iPSCs into GABAminergic neurons, Hirose’s laboratory made a model system for DS patients that could be grown in a laboratory culture dish.

Hirose explained their results this way: “From research in mice we believed that SCN1A mutations affect GABAminergic neurons in the forebrain from signaling properly. From the human neurons we also found that GABAminergic neurons were affected by DS, especially during intense stimulation. These patient-specific cell provide an unparalleled insight into the mechanism behind DS and a unique platform for drug development.”

Perhaps such experiments could eventually lead to regenerative treatments for DS patients as well.