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Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress.
Introduction
Mental stress can have different effects on the nervous system. While brief mild stress can evoke emotional arousal and enhance learning (1), chronic elevated stress can induce deficits in neuronal function (2, 3). 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 (4, 5). Because of the complex and poorly understood regulation of neuronal functions by stress (6, 7), elucidation of how stress affects the nervous system at the molecular, cellular, and circuit levels is an important step in controlling stress disorders.
Experience early in postnatal life is important to the establishment of normal functioning cortical circuits (8, 9). During this period, sensory experience through whiskers, an important form of social communication in rodents (10, 1 1), leads to a several-fold increase in excitatory synaptic transmission in the barrel cortex (12).
Excitatory synaptic transmission in the central nervous system is mainly mediated by a-amino-3-hydroxy-5-methylisoxazole-4propionic acid-type (AMPA-type) glutamate receptors (13, 14). The number of AMPA receptors at synaptic sites determines the synaptic responses of postsynaptic neurons and controls neuronal activity (14-18). Stimuli inducing synaptic plasticity such as long-term potentiation (LTP) drive GluRl-containing AMPA receptors into synapses in vitro (19, 20). In vivo, whisker experience drives GIuRl -containing AMPA receptors into...