Disrupted cortical function underlies behavior dysfunction due to social isolation.
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.
Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Tomoyuki
T
Miyazaki
Kenkichi
K
Takase
Waki
W
Nakajima
Hirobumi
H
Tada
Daisuke
D
Ohya
Akane
A
Sano
Takahisa
T
Goto
Hajime
H
Hirase
Roberto
R
Malinow
Takuya
T
Takahashi
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D005260:Female; D005938:Glucocorticoids / Q000097:blood; D017774:Long-Term Potentiation; D008297:Male; D009473:Neuronal Plasticity; D009638:Norepinephrine / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D012683:Sensory Deprivation; D012934:Social Isolation; D013003:Somatosensory Cortex / Q000378:metabolism / Q000502:physiology*; D013315:Stress, Psychological; D009435:Synaptic Transmission; D055698:Touch Perception; D014738:Vibrissae / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003345:Corticosterone; D005938:Glucocorticoids; D009638:Norepinephrine; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid