Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia and
depression. In schizophrenia, deficits have been particularly well-described for a subtype of GABA
neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical for proper cognitive and emotional
functioning.
It now appears that parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that may emerge commonly in
development, particularly in the context of psychiatric disorders like schizophrenia or bipolar
disorder, where compromised mitochondrial function plays a
role.
Parvalbumin neurons may be protected from this effect by
N-acetylcysteine, also known as Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of acetaminophen
(Tylenol) overdose, reports a new study in the current issue of Biological
Psychiatry.
Dr. Kim Do and collaborators, from the Center for Psychiatric Neurosciences of Lausanne University in
Switzerland, have worked many years on the hypothesis that one of the causes of schizophrenia is related to vulnerability
genes/factors leading to oxidative stress. These oxidative stresses can be due to
infections, inflammations, traumas or psychosocial stress occurring during typical brain
development, meaning that at-risk subjects are particularly exposed during childhood and
adolescence, but not once they reach adulthood.
Their study was performed with mice deficient in
glutathione, a molecule essential for cellular protection against
oxidations, leaving their neurons more exposed to the deleterious effects of oxidative stress. Under those
conditions, they found that the parvalbumin neurons were impaired in the brains of mice that were stressed when they were
young. These impairments persisted through their life.
Interestingly, the same stresses applied to adults had no effect on their parvalbumin
neurons.
Most strikingly, mice treated with the antioxidant
N-acetylcysteine, from before birth and onwards, were fully protected against these negative consequences on parvalbumin
neurons.
"These data highlight the need to develop novel therapeutic approaches based on antioxidant compounds such as
N-acetylcysteine, which could be used preventively in young at-risk
subjects," said Do. "To give an antioxidant from childhood on to carriers of a genetic vulnerability for schizophrenia could reduce the risk of emergence of the
disease."
"This study raises the possibility that GABA neuronal deficits in psychiatric disorder may be preventable using a
drug, N-acetylcysteine, which is quite safe to administer to
humans," added Dr. John Krystal, Editor of Biological
Psychiatry.
For more information
Biological Psychiatry
The article is "Early-Life Insults Impair Parvalbumin Interneurons via Oxidative Stress: Reversal by
N-Acetylcysteine" by Jan-Harry Cabungcal, Pascal
Steullet, Rudolf Kraftsik, Michel Cuenod, and Kim Q. Do
(doi: 10.1016/j.biopsych.2012.09.020)
http://www.ncbi.nlm.nih.gov/pubmed/23140664
Elsevier
http://www.elsevier.com/
(MDN)
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