GABA_A receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: Possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Figures & data

Figure 1 Schematic drawing of putative mechanism underlying social isolation-induced behavioral abnormalities and neurosteroid downregulation. (A) GABAergic neurotransmission in group-housed mice. ALLO synthesized by 5α-reductase type I and 3α-HSD at physiologically relevant concentrations positively modulates the action of GABA at GABA_A-R, thereby exhibiting permissive action in the regulation of pentobarbital-induced sedation (bold, larger font) and suppressing aggression (smaller font), respectively. (B) GABAergic neurotransmission in socially isolated male mice: protracted social isolation (for 4 weeks or more) causes i) downregulation of 5α-reductase I expression and reduced brain ALLO content (indicated by a smaller font) and ii) alterations of GABA_A-R subunit expression (i.e. decreases in α1-, α2-, and γ2-subunit and increases in α4- and α5-subunits), thereby reducing GABA_A-R function. The decrease in GABA_A-R-mediated signal transduction contributes to behavioral abnormalities; i.e. decreases in pentobarbital sedation (small font) and increases in aggressiveness (bold font). (C) FLX and Nor-FLX-induced amelioration of neurosteroid downregulation and behavioral abnormalities caused by social isolation. FLX and Nor-FLX ameliorate pentobarbital sedation and reduce aggressiveness, presumably by activating 5α-reductase type I and by correcting the reduced level of brain ALLO content, thereby normalizing GABA_A-R-mediated signal transduction.

Table I.  Social isolation-induced decrease in the turnover rate of 5α-DHP and 3α,5α-THP biosynthesis in the brain.

Housing condition	5α-DHP (pmol/g/h)	ALLO (pmol/g/h)
Group-housed	27 ± 3.1	28 ± 3.6
Socially isolated	9.4 ± 0.9*	11 ± 2.5*

Mice group-housed or socially isolated for 6 weeks were treated with SKF105111, a selective 5α-reductase type I and II inhibitor (48 μmol/kg, i.p.). The turnover rates of 5α-DHP and 3α,5α-THP in the frontal cortex were calculated from semilogarithmic plots of decline curves of 5α-DHP and 3α,5α-THP contents after SKF105111. Each represents the mean ± SEM from 5 to 6 mice. *P < 0.01 compared with the values from group-housed animals (adapted from Dong et al. 2001).

Table II.  Social isolation reduces brain ALLO content by downregulating 5α-reductase type I expression in the brain.

Housing condition	Type I 5α-reductase mRNA (attomol/mg RNA)	5α-Reductase/β actin (OD ratio, × 10^− 2)	3α-HSD mRNA (attomol/mg RNA)
Group-housed	73.9 ± 4.4	12.1 ± 3.0	12.1 ± 1.2
Socially isolated	39.8 ± 3.7*	4.5 ± 1.8*	11.4 ± 0.7

Each value represents the mean ± SEM from 5 to 6 mice either group-housed or socially isolated for 6 weeks. *P < 0.01 compared with the values of group-housed mice (adapted from Dong et al. 2001).

Table III.  Expression levels of GABA_A-R subunit mRNAs in the frontal cortex of group-housed and socially isolated mice.

GABAA subunit	Housing condition
	Group-housed	Socially isolated
α1	1511.7 ± 169.7	748.3 ± 127.3**
α2	430.5 ± 53.1	271.7 ± 47.7*
α3	356.9 ± 42.4	335.9 ± 63.7
α4	87.1 ± 31.8	198.7 ± 42.4**
α5	278.6 ± 53.0	655.3 ± 111.4*
β3	989.8 ± 137.9	1154.5 ± 164.4
γ2	343.5 ± 52.6	190.0 ± 31.8
δ	121.4 ± 31.8	105.7 ± 31.8

Male mice were housed in groups or socially isolated for 4 weeks before the start of the experiments. Each value (attomol/μg RNA) represents the mean ± SEM of five mice. *P < 0.05 and **P < 0.01 compared with group-housed animals (adopted from Pinna et al. PNAS 2006a).

Figure 2 Quantitative nested PCR analysis coupled with laser capture microdissection of α1 subunit mRNA in frontal cortical layers I and V of mice that were group-housed or socially isolated for 4 weeks. Cortical layer I and pyramidal cell somata located in layer V were microdissected using a laser capture method. GABA_A-R α1 subunit mRNA in total RNA extracted from dissected tissue was determined by competitive RT-RTPCR associated with nested PCR. Each datum represents the mean ± SEM. of four mice. *P < 0.01 compared with group-housed mice.

Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A. Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci USA 2001; 98: 2849–2854

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