New findings reverse hypothesis of GABA neurodevelopment in schizophrenia

June 20, 2017
Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.

New research by scientists at the University of Pittsburgh provides an unprecedented level of resolution and insight into disturbances in cortical GABAergic microcircuits, which are thought to underlie cognitive impairments in schizophrenia. Published in Biological Psychiatry, the study led by Dr. Kenneth Fish reveals new detailed understanding about alterations in neurocircuitry that point to abnormal neurodevelopment in the disorder.

A recent generation of studies of postmortem brain tissue from people with schizophrenia, particularly from the laboratory of Professor David Lewis and his colleagues at the University of Pittsburgh, have shed light on schizophrenia-related abnormalities in the interplay of the main excitatory neurons, pyramidal neurons, and a specific class of inhibitory nerve , called , in the . Chandelier cells tune the activity of by releasing the inhibitory transmitter GABA through complex arrays of connections called cartridges. Prior postmortem studies have led to the hypothesis that most cartridges across 2-5 have a decreased level of GABA reuptake, presumably a compensatory mechanism for lower GABA signaling associated with the disorder. However, the new postmortem study from the same group found evidence suggesting that the ability of chandelier cells to synthesize and release GABA within the prefrontal cortex is unaltered in schizophrenia. The study also demonstrates that the density of a specific subclass of chandelier cell cartridges is higher exclusively in layer 2 in the disease.

In the study, first author Brad Rocco, a graduate student in Fish's laboratory, and colleagues compared GABA synthesizing and packaging proteins within chandelier cell cartridges, as well as the density of these cartridges in the prefrontal cortex of 20 schizophrenia subjects and 20 comparison subjects. In layer 2, the density of cartridges arising from a transcriptionally-unique subset of chandelier cells containing calbindin was nearly 3-fold higher in the schizophrenia group. This subset only comprises a small fraction of neurons in the prefrontal cortex. In contrast, there was no difference in the density of chandelier cell cartridges lacking calbindin in layer 2 or in either type of across layers 3-6.

"These findings challenge prior studies that suggested that GABA deficits were a relatively universal feature of schizophrenia," said Dr. John Krystal, Editor of Biological Psychiatry.

The study was unable to determine the cause of this increased cartridge density, but the researchers suspect a developmental origin based on the layer specificity of the findings. Chandelier cell cartridges undergo dramatic pruning during development, and 2 matures much later than the deeper cortical layers, which had normal cartridge densities. "This finding suggests that the normal developmental pruning of these cartridges might be blunted in ," said Fish.

According to Fish, substantial resources are being invested in the identification of transcriptionally-unique subtypes of human brain cells, an essential element in understanding the human brain, and the new findings highlight the importance of studying these types of cells in psychiatric disease. "The long-term goal of these efforts is to identify new ways to treat, cure, and even prevent brain disorders," said Fish.

Explore further: Distinct wiring mode found in chandelier cells

More information: Brad R. Rocco et al, Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia, Biological Psychiatry (2017). DOI: 10.1016/j.biopsych.2016.09.018

Related Stories

Distinct wiring mode found in chandelier cells

June 9, 2017
A basic tenet of neural development is that young neurons make far more connections than they will actually use, with very little specificity. They selectively maintain only the ones that they end up needing. Once many of ...

Scientists discover two proteins that control chandelier cell architecture

January 16, 2014
Chandelier cells are neurons that use their unique shape to act like master circuit breakers in the brain's cerebral cortex. These cells have dozens, often hundreds, of branching axonal projections – output channels from ...

More brain activity is not always better when it comes to memory and attention

June 13, 2017
Potential new ways of understanding the cause of cognitive impairments, such as problems with memory and attention, in brain disorders including schizophrenia and Alzheimer's are under the spotlight in a new research review.

Study could help explain link between seizures and psychiatric disorders

June 6, 2017
In a new study published in Cell Reports, scientists at the Gladstone Institutes identified different types of neurons in a brain region called the reticular thalamus. A better understanding of these cells could eventually ...

Recommended for you

Communicating in a foreign language takes emotion out of decision making

August 16, 2017
If you could save the lives of five people by pushing another bystander in front of a train to his death, would you do it? And should it make any difference if that choice is presented in a language you speak, but isn't your ...

Precision medicine opens the door to scientific wellness preventive approaches to suicide

August 15, 2017
Researchers have developed a more precise way of diagnosing suicide risk, by developing blood tests that work in everybody, as well as more personalized blood tests for different subtypes of suicidality that they have newly ...

US antidepressant use jumps 65 percent in 15 years

August 15, 2017
(HealthDay)—The number of Americans who say they've taken an antidepressant over the past month rose by 65 percent between 1999 and 2014, a new government survey finds.

Child's home learning environment predicts 5th grade academic skills

August 15, 2017
Children whose parents provide them with learning materials like books and toys and engage them in learning activities and meaningful conversations in infancy and toddlerhood are likely to develop early cognitive skills that ...

Obesity and depression are entwined, yet scientists don't know why

August 15, 2017
About 15 years ago, Dr. Sue McElroy, a psychiatrist in Mason, Ohio, started noticing a pattern. People came to see her because they were depressed, but they frequently had a more visible ailment as well: They were heavy.

Givers really are happier than takers

August 15, 2017
(HealthDay)—Generosity really is its own reward, with the brain seemingly hardwired for happiness in response to giving, new research suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.