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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Research Article Neuroscience

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 4

Mechanisms underlying isolation-induced disruption of synaptic AMPA receptor delivery.

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Mechanisms underlying isolation-induced disruption of synaptic AMPA rece...
(A) Immunohistostaining of the barrel cortex of animals at P11 with anti-GR antibody. (B) Nuclear fraction contained larger amount of GR at 3 hours after social isolation than nonisolated animals. The amount of GR in the nuclear fraction of isolated animals was normalized to nonisolated rats (*P < 0.05, isolated vs. nonisolated; n = 6 per each group). (C) Local injection of RU486 during social isolation prevented the disruption of synaptic GluR1 delivery by social isolation. Top inset showed time line of experimental manipulations (see text) (*P < 0.05, R1 versus non; n = 9 isolated with RU486, n = 7 isolated with vehicle). (D) Social isolation decreased phosphorylation of CaMKII at Thr286 compared with nonisolated rats. Phosphorylation level (calculated as the ratio to total CaMKII) of rats with social isolation in the presence of RU486 was comparable to nonisolated rats (F(2,11) = 8.163, *P < 0.05; n = 5 per each group). (E) Social isolation decreased phosphorylation of Ser831 of GluR1 compared with nonisolated rats. Phosphorylation level of rats with social isolation in the presence of RU486 was comparable to nonisolated rats but larger than isolated animals without RU486 (F(2,45) = 6.950, *P < 0.05; n = 12 per each group). (F) No delivery of 831A (R1 831A) at layer 4-2/3 synapses in the barrel cortex of intact rats at P12–P14 (n = 16). Scale bars: 200 μm (A); 100 μm (A, inset); 10 pA/20 ms. (B, D, and E); 20 pA/20 ms (C). Lanes were run on the same gel but are noncontiguous. Data were analyzed by paired, 2-tailed t test (B, C, F) or 1-way factorial ANOVA (D, E).