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How to normalise synapses in autism & schizophrenia

Targeted drug therapies during adolescence may be used to normalize synapse number in the brains of those with Autism and Schizophrenia who have abnormal numbers of synapses.

Memories are formed at structures in the brain known as dendritic spines, small protrusions off of neurons that allow signals to transmit to other neurons through "synapses."

The number of dendritic spines decreases by 50% after puberty in a process called adolescent "synaptic pruning" and must occur for normal adult learning.

Pruning of unnecessary synapses doesn't happen normally in autism and schizophrenia. This abnormality may underlie many cognitive impairments associated with these two disorders.

Researchers at SUNY Downstate Medical Center had recently discovered an inhibitory brain receptor that triggers synaptic pruning in adolescence. Now new research from SUNY finds drugs, when administered in adolescence, selectively target inhibitory brain receptors and can alter synapse numbers.

According to Sheryl S. Smith PhD, and professor of physiology and pharmacology at SUNY Downstate, "Drugs that enhance activity of this inhibitory receptor reduce synapse number, while drugs that decrease this inhibitory receptor increase synapse number."

This article "α4βδ GABAA receptors reduce dendritic spine density in CA1 hippocampus and impair relearning ability of adolescent female mice: Effects of a GABA agonist and a stress steroid," by Sonia Afroz, Hui Shen, Sheryl S. Smith, appears in Neuroscience, Volume 347 (April 2017), published by Elsevier. It can be accessed on PubMed.gov.

"These findings suggest that targeted drug therapies during adolescence could potentially be used to normalize synapse number in the brains of individuals with abnormal numbers of synapses, such as found in autism and schizophrenia."

Sheryl S. Smith PhD, Professor, Physiology and Pharmacology, SUNY Downstate

Dr. Smith cautions, however, that at this time such drugs are not yet available for use in humans.

Related article: Safe, inexpensive chemical reverses progeria

Increasing ?4?? GABAA receptor current with gaboxadol during puberty decreases dendritic spine density in adulthood.
Decreasing ?4?? GABAA receptor expression with THP during puberty increases dendritic spine density in adulthood.
Abnormal spine density produced by pubertal drug treatments impairs re-learning a spatial memory task in the adult.
These findings suggest that ?4?? GABAA receptors are a novel target to normalize spine density in adolescence.
These results may suggest new therapies for autism and schizophrenia where spine density and cognition are abnormal.

Synaptic pruning underlies the transition from an immature to an adult CNS through refinements of neuronal circuits. Our recent study indicates that pubertal synaptic pruning is triggered by the inhibition generated by extrasynaptic ?4?? GABAA receptors (GABARs) which are increased for 10 d on dendritic spines of CA1 pyramidal cells at the onset of puberty (PND 35-44) in the female mouse, suggesting ?4?? GABARs as a novel target for the regulation of adolescent synaptic pruning. In the present study we used a pharmacological approach to further examine the role of these receptors in altering spine density during puberty of female mice and the impact of these changes on spatial learning, assessed in adulthood. Two drugs were chronically administered during the pubertal period (PND 35-44): the GABA agonist gaboxadol (GBX, 0.1mg/kg, i.p.), to enhance current gated by ?4?? GABARs and the neurosteroid/stress steroid THP (3?-OH-5?-pregnan-20-one, 10mg/kg, i.p.) to decrease expression of ?4??. Spine density was determined on PND 56 with Golgi staining. Spatial learning and relearning were assessed using the multiple object relocation task and an active place avoidance task on PND 56. Pubertal GBX decreased spine density post-pubertally by 70% (P<0.05), while decreasing ?4?? expression with THP increased spine density by twofold (P<0.05), in both cases, with greatest effects on the mushroom spines. Adult relearning ability was compromised in both hippocampus-dependent tasks after pubertal administration of either drug. These findings suggest that an optimal spine density produced by ?4?? GABARs is necessary for optimal cognition in adults.

The article is "α4βδ GABAA receptors reduce dendritic spine density in CA1 hippocampus and impair relearning ability of adolescent female mice: Effects of a GABA agonist and a stress steroid," by Sonia Afroz, Hui Shen, Sheryl S. Smith. It appears in Neuroscience, Volume 347 (April 2017), published by Elsevier on PubMed.gov.

Key words: GABA-A receptor; alpha4; delta; gaboxadol; allopregnanolone; synaptic pruning

The research leading to the results published by Neuroscience was supported by the National Institutes of Health/National Institute of Mental Health, Award Number R01-MH100561, to Sheryl S. Smith. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or National Institutes of Health. Copies of this paper are available to credentialed journalists upon request; please contact Elsevier's Newsroom at newsroom@elsevier.com or +31 20 485 2492.

About SUNY Downstate
SUNY Downstate Medical Center, founded in 1860, was the first medical school in the United States to bring teaching out of the lecture hall and to the patient's bedside. A center of innovation and excellence in research and clinical service delivery, SUNY Downstate Medical Center comprises a College of Medicine, College of Nursing, College of Health Related Professions, a School of Graduate Studies, a School of Public Health, University Hospital of Brooklyn, and a multifaceted biotechnology initiative including the Downstate Biotechnology Incubator and BioBAT for early-stage and more mature companies, respectively. SUNY Downstate ranks twelfth nationally in the number of alumni who are on the faculty of American medical schools. More physicians practicing in New York City have graduated from SUNY Downstate than from any other medical school. For more information, visit http://www.downstate.edu.

About Neuroscience
An International Journal under the editorial direction of IBRO, Neuroscience publishes papers describing the results of original research on any aspect of the scientific study of the nervous system. Any paper, however short, will be considered for publication provided that it reports significant, new and carefully confirmed findings with full experimental details.
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