Disrupted cortical function underlies behavior dysfunction due to social isolation
Tomoyuki Miyazaki, … , Roberto Malinow, Takuya Takahashi
Tomoyuki Miyazaki, … , Roberto Malinow, Takuya Takahashi
Published June 18, 2012
Citation Information: J Clin Invest. 2012;122(7):2690-2701. https://doi.org/10.1172/JCI63060.
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Disrupted cortical function underlies behavior dysfunction due to social isolation

Abstract

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.

Authors

Tomoyuki Miyazaki, Kenkichi Takase, Waki Nakajima, Hirobumi Tada, Daisuke Ohya, Akane Sano, Takahisa Goto, Hajime Hirase, Roberto Malinow, Takuya Takahashi

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Figure 1

Social isolation disrupts experience-dependent synaptic delivery of AMPA receptors in the developing rat barrel cortex.

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Social isolation disrupts experience-dependent synaptic delivery of AMPA...
(A–C) Top insets: time line of experiments. R1, GFP-GluR1–expressing neurons; non, nonexpressing neurons. (A) Isolation during P7–P11 disrupted GluR1 delivery at P12–P14 (*P < 0.05, R1 versus non; n = 8 nonisolated control, n = 9 isolated). (B) Removal of mother during P7–P11 (mother removed) did not disrupt GluR1 delivery at P12–P14 (*P < 0.05, R1 versus non; n = 8) (left). Blockade of whisker input during removal of mother (whisker mask) did not prevent GluR1 delivery (*P < 0.05, R1 versus non; n = 5) (right). (C) Isolation (P4–P7) disrupted GluR1 delivery during P12–P14 (*P < 0.05, R1 versus non; n = 6). (D) A/N ratio at P14 was lower with rats isolated than nonisolated rats (*P < 0.05, isolated vs, nonisolated; n = 18). (E) A/N ratio at P14 of pups, either mother removed or whisker masked, was comparable with nonisolated rats, but larger than isolated animals (n = 16) (*P < 0.05, compared with nonisolated [n = 15], mother removed [n = 17], whisker mask [n = 21] animals; F(3,65) = 4.022). (F) A/N ratio at P14 was lower with rats isolated at P4–P7 than nonisolated rats (*P < 0.05, isolated vs. nonisolated; n = 15 nonisolated control animals, n = 18 isolated animals). Scale bars: 20 pA/20 ms (A, D); 10 pA/20 ms (B); 10 pA/15 ms (E, F). Data were analyzed by paired, 2-tailed t test (A–D, F) or 1-way factorial ANOVA (E).