Social isolation‐induced increase in NMDA receptors in the hippocampus exacerbates emotional dysregulation in mice

Abstract

Epidemiological studies have shown that early life adverse events have long-term effects on the susceptibility to subsequent stress exposure in adolescence, but the precise mechanism is unclear. In the present study, mice on postnatal day 21-28 were randomly assigned to either a group or isolated cages for 8 weeks. The socially isolated (SI) mice exhibited a higher level of spontaneous locomotor activity, a longer duration of immobility in the forced swimming test (FST), significantly less prepulse inhibition (PPI) and an increase in aggressive (but not attack) behavior. However, acute stress markedly exacerbated the attack counts of the SI mice but did not affect the group housing (GH) mice. SI mice exhibited higher synaptosomal NR2A and NR2B levels in the hippocampus as compared to the GH mice. Whole-cell patch clamp recordings of CA1 neurons in hippocampal slices showed that the SI mice exhibited a higher input-output relationship of NMDAR-EPSCs as compared to the GH mice. Application of the NR2B -specific antagonist ifenprodil produced a greater attenuating effect on NMDAR-EPSCs in slices from the SI mice. NMDAR EPSCs recorded from the SI mice had a slower deactivation kinetic. MK-801, CPP and ifenprodil, the NMDA antagonists, reversed acute stress-induced exaggeration of aggressive and depressive behaviors. Furthermore, acute stress-induced exacerbation of attack behavior in the SI mice was abolished after the knockdown of NR2B expression. These results suggest that social isolation-induced increased expression of NMDA receptors in the hippocampus involves stress exacerbation of aggressive behaviors. Amelioration of aggressive behaviors by NMDA antagonists may open a new avenue for the treatment of psychopathologies that involve outbursts of emotional aggression in neglected children.

Chronic Monoarthritis Pain Accelerates the Processes of Cognitive Impairment and Increases the NMDAR Subunits NR2B in CA3 of Hippocampus from 5-month-old Transgenic APP/PS1 Mice

“…Chronic early postnatal scream sound stress upregulates NR2B levels in the CA1 and CA3, downregulates the NR2A/NR2B ratio, and impairs spatial learning and memory in male mice (Hu et al, 2016). Social isolation stress exacerbates aggressive behaviors and increases NR2A and NR2B levels in the hippocampus (Chang et al, 2015). The activation of extrasynaptic NR2B is involved in the Aβ-induced impairment of LTP in hippocampal slices (Ondrejcak et al, 2010; Li et al, 2011; Rönicke et al, 2011).…”

Finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress

“…Previous studies have shown that distinct acute or chronic stress paradigms can decrease PPI responses. This effect of stress on PPI has been described in social isolated mice [8] and Wistar [9] or female LongEvans hooded rats [10], after acute restraint stress in C57BL/6 mice [11] or repeated restraint stress in Brown Norway rats [12], and http://dx.doi.org/10.1016/j.bbr.2015.04.023 0166-4328/© 2015 Elsevier B.V. All rights reserved. after rapid eye movement sleep deprivation [13] or predator exposure [14] in male Sprague-Dawley rats.…”

5‐HT2CR antagonist/5‐HT2CR inverse agonist recovered the increased isolation‐induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing

“…Previous studies have reported that social isolation stress is one of the major factors resulting in enhanced aggressive behavior. Social isolation led to enhanced aggressive behavior in C57BL/6j mice (Chang, Hsiao, Chen, Yu, & Gean, ; Dang et al., ; Ma, Jiang, Jiang, Wang, & Jia, ), ICR mice (Ouchi, Ono, Murakami, & Matsumoto, ; Yokota, Oshio, Moriya, & Takeda, ), ddY mice (Kawasaki et al., ; Vekovischeva, Verbitskaya, Aitta‐Aho, Sandnabba, & Korpi, ), and Swiss mice (Vekovischeva et al., ). The present findings provided evidence that 2‐week social isolation stress increased the aggressive behavior of BALB/c mice.…”