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Is Under-Developed Inhibition in the Brain’s Communication System Linked to Schizophrenia?

 

Researchers at the Lieber Institute for Brain Development (LIBD), with colleagues, have studied hundreds of donated human brains, across the life span.  

Researchers at the Lieber Institute for Brain Development (LIBD), with colleagues, have studied hundreds of donated human brains, across the life span. In their work, they are trying to decode what happens during brain development that ultimately leads to schizophrenia. 

In work published in the Journal of Neuroscience on July 27, 2011, the research team, including scientists from LIBD, the National Institute of Mental Health and Johns Hopkins, investigated the most common inhibitory neurotransmitter in the brain, called GABA. Neurotransmitters are chemicals that relay signals between nerve cells to enable communication; they are either excitatory, and stimulate the brain, or are inhibitory, and calm the brain. Inhibitory neurotransmitters are easily depleted when excitatory neurotransmitters are overactive and abnormalities in GABA signaling have previously been linked to schizophrenia.

The researchers here sought to investigate whether the pattern of GABA abnormalities associated with schizophrenia reflect genetically regulated developmental processes. They examined the expression (“transcription”) of four molecules that are part of the machinery of GABA signaling—GAD67, GAD25, NKCC1, and KCC2—in the prefrontal cortex (PFC) and hippocampus regions in the brains of normal control subjects across the lifespan and in patients with schizophrenia. They discovered that healthy development and maturation of both the PFC and hippocampus depend on progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2.

The researchers observed that GAD25/GAD67 and NKCC1/KCC2 ratios in the hippocampus were increased in individuals with schizophrenia …reflecting a potentially under-developed GABA system.

Previous studies have demonstrated that the switch from GAD25 to GAD67 initiates the production of GABA, and the switch from NKCC1 to KCC2 results in GABA transitioning from an excitatory to an inhibitory neurotransmitter. The transition of GABA from excitation to inhibition is critical to healthy brain development. Here, the researchers observed that GAD25/GAD67 and NKCC1/KCC2 ratios in the hippocampus were increased in individuals with schizophrenia relative to controls, reflecting a potentially under-developed GABA system in patients with schizophrenia.

Notably, increased GAD25/GAD67 and NKCC1/KCC2 expression ratios were associated with a small variation in the gene that encodes GAD25 and GAD67. This genetic variation is commonly found in people with schizophrenia, and its association with relative overexpression of GAD25 suggests that the mechanism of genetic risk involves an immature developmental profile in GABA neurons.

To address the issue of whether the expression levels of GABA-related molecules could have been affected by the patients’ use of anti-psychotic medications, the researchers measured the expression of NKCC1 and KCC2 in rats treated with haloperidol and clozapine. Neither medication affected the expression of NKCC1, KCC2, or the NKCC1/KCC2 ratio, suggesting that the expression ratios observed in the human subjects were not likely to have been affected by the use of either medication.