Mechanisms underlying the effect of neonatal social isolation on brain function

Posted on Posted in AMRC Research

Date: 19 Jun 2012

 

Mental stress can have different effects on the nervous system. While brief mild stress can evoke emotional arousal and enhance learning, chronic elevated stress can induce deficits in neuronal function. In particular, social isolation early in life caused by neglect (a form of child abuse), can induce mental stress and lead to various mental illnesses such as depression, drug addiction, and anxiety disorders. Because of the complex and poorly understood regulation of neuronal functions by stress, elucidation of how stress affects the nervous system at the molecular, cellular and circuit levels is an important step to control stress disorders.

Professor Takuya Takahashi and his colleagues at Yokohama City University (and Albert Einstein College of Medicine, NY, USA) present a comprehensive study that explains how neonatal social isolation stress affects brain function in the rat at a molecular and cellular level. Understanding the molecular mechanism through which neonatal abusive stress affects brain circuit formation will further our knowledge of how to selectively control mental disorders induced by neonatal maltreatment.

This study will be published in the July issue of Journal of Clinical Investigation (June 18th 2012, 12:00 PM EST online ) .

This study was mainly funded by “Development of biomarker candidates for social behavior” carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports,Science and Technology of Japan, and Special Coordination Funds for Promoting Science and Technology.


Background and results

The majority of excitatory synapses in the mammalian central nervous system use glutamate as a neurotransmitter. Fast glutamatergic transmission is mainly mediated by AMPA (α-amino-3-hydroxy- 5-methyl-4-isoxazole propionic acid) type ionotropic glutamate receptors (AMPARs) (Figure). AMPARs are tetramers comprised of a combinatorial assembly of four subunits, GluR1-4. Synaptic plasticity at glutamatergic synapses is considered to be crucial for cognitive functions such as learning and memory. The best-studied form of synaptic plasticity is LTP (Long-term potentiation), and its molecular mechanisms have been extensively characterized. Synaptic delivery and addition of AMPARs appears to be a major mechanism regulating postsynaptic expression of LTP. LTP inducing stimuli in vitro drive GluR1-containing AMPARs into synapses and enhance synaptic transmission. The same molecular modification occurs during experience-dependent neuronal reorganization in vivo (Figure). Sensory experience early in development delivers GluR1 into synapses of the rodent barrel cortex which receives input from whiskers.

In this study, Professor Takuya Takahashi and his colleagues at Yokohama City University (and Albert Einstein College of Medicine, NY, USA) showed that neonatal isolation prevents long-term potentiation and experience-dependent synaptic trafficking of AMPA receptors normally occurring during circuit formation in the rodent barrel cortex. This is mediated by an increase of the stress glucocorticoid hormone, reduced CaMKII signaling, and results in the corruption of the sensory mapping onto cortex. These effects during early life lead to defects in whisker-dependent behavior (Figure).


Future perspectives

This study presents the molecular and cellular mechanisms underlying how neonatal abusive stress affects brain circuit formation. This will further our knowledge of how to selectively control mental disorders induced by neonatal maltreatment.

 

Model of the molecular and cellular mechanisms underlying contextual fear memory formation.
Model of the molecular and cellular mechanisms underlying contextual fear memory formation.

 

For inquiries regarding this press release

Takuya Takahashi M.D. Ph.D
Professor, Department of Physiology, Graduate School of Medicine, Yokohama City University
Tel: 81-45-787-2577
FAX: 81-45-787-2580
e-mail: takahast@yokohama-cu.ac.jp