Neurosteroid Treatment Reduces Schizophrenia-Like Symptoms in Mice

Neurosteroid Treatment Reduces Schizophrenia-Like Symptoms in Mice

Posted: April 13, 2015

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Using a mouse model, scientists have found that the steroid pregnenolone sulfate reduces both behavioral and cognitive symptoms like those seen in schizophrenia. The research was published March 17th in the journal Translational Psychiatry.

In people, antipsychotic medications can control the delusions and hallucinations of schizophrenia. But they do little to overcome the disorder's behavioral and cognitive symptoms, which can include movement disorders and problems with memory, attention, motivation, and decision-making. The new research was led by two-time (2006, 2008) NARSAD Independent Investigator grantee Xiaodong Zhang, at Duke-National University of Singapore Graduate Medical School. Dr. Zhang and colleagues found that movement problems and impaired responses to startling stimuli responded quickly to treatment with pregnenolone sulfate. Problems with memory and discrimination tasks lessened with long-term treatment.

Pregnenolone sulfate belongs to a family of chemicals called neurosteroids, which are produced naturally in the brain and help regulate communication between nerve cells. Various neurosteroids, including pregnenolone––a molecular precursor of the steroid used in this study––have been found to be present at abnormal levels (some higher, some lower) in people with schizophrenia. Pregnenolone is much more concentrated than pregnenolone sulfate.

Previously, researchers observed in animal studies and in clinical trials with small groups of patients that treatment with pregnenolone can improve some of the behavioral symptoms of schizophrenia such as flat affect and difficulty in socializing. Dr. Zhang and his colleagues suspected that boosting levels of the less powerful pregnenolone sulfate might have similar benefits. They also knew that pregnenolone sulfate had been shown to enhance learning and memory in mice.

The team administered pregnenolone sulfate to mice with a genetic mutation that causes schizophrenia-like symptoms including movement problems, altered responses to startling stimuli, memory impairment, and other cognitive deficiencies. The researchers then examined the effects. Within a few hours of treatment, abnormal movement and defects with the response to startling stimuli were eliminated. After 10 days of treatment with pregnenolone sulfate, animals performed better on tests of cogntive abilities and memory.

In further experiments, the scientists found evidence that pregnenolone sulfate acts on cellular signaling pathways that stimulate the production of a part of the cellular docking ports called NMDA receptors. These receptors are critical for memory formation; they are less active than normal in the brains of people with schizophrenia. The steroid's impact on NMDA receptor production could explain the positive treatment outcomes they observed in the mice, the scientists say.

Read the paper.