Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice

Abstract

Allopregnanolone (ALLO), synthesized by pyramidal neurons, is a potent positive allosteric modulator of the action of GABA at GABAA receptors expressing specific neurosteroid binding sites. In the brain, ALLO is synthesized from progesterone by the sequential action of two enzymes: 5␣-reductase type I (5␣-RI) and 3␣-hydroxysteroid dehydrogenase (3␣-HSD). In the cortex, hippocampus, and amygdala, these enzymes are colocalized in principal glutamatergic output neurons [Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006) Proc Natl Acad Sci USA 103:14602-14607], but they are not detectable in GABAergic interneurons. Using RT-PCR and in situ hybridization, this study compares 5␣-RI and 3␣-HSD mRNA brain expression levels in group housed and in socially isolated male mice for 4 weeks. In these socially isolated mice, the mRNA expression of 5␣-RI was dramatically decreased in hippocampal CA3 glutamatergic pyramidal neurons, dentate gyrus granule cells, glutamatergic neurons of the basolateral amygdala, and glutamatergic pyramidal neurons of layer V/VI frontal (prelimbic, infralimbic) cortex (FC). In contrast, 5␣-RI mRNA expression failed to change in CA1 pyramidal neurons, central amygdala neurons, pyramidal neurons of layer II/III FC, ventromedial thalamic nucleus neurons, and striatal medium spiny and reticular thalamic nucleus neurons. Importantly, 3␣-HSD mRNA expression was unchanged by protracted social isolation (Si). These data suggest that, in male mice, after 4 weeks of Si, the expression of 5␣-RI mRNA, which is the rate-limiting-step enzyme of ALLO biosynthesis, is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. In socially isolated mice, this down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.5␣-reductase ͉ amygdala ͉ glutamatergic neurons ͉ allopregnanolone ͉ aggression

Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder

“…Using an in situ hybridization technique to detect 5␣-RI mRNA in neurons, we found that the transcript of this enzyme was dramatically decreased in hippocampal CA3 glutamatergic pyramidal neurons, dentate gyrus granule cells, glutamatergic pyramidal-like neurons of the BLA, and in layers V/VI glutamatergic pyramidal neurons of the mPFC of mice socially isolated for 4 weeks (8). In contrast, 5␣-RI mRNA expression failed to change in CA1 pyramidal neurons, pyramidal neurons of layers II/III mPFC, ventromedial thalamic nucleus neurons, or striatal medium spiny and reticular thalamic nucleus neurons (8). Taken together, these data suggest that in socially isolated mice the expression of Allo is specifically down-regulated in glutamatergic pyramidal neurons that converge on the BLA from the mPFC and hippocampus.…”

“…Taken together, these findings suggest that a down-regulation of Allo biosynthesis in corticolimbic GABAergic synapses may be an important component in eliciting aggression and anxiety-like behavior (8,13).…”

“…A 5␣-RI mRNA expression reduction occurs selectively in glutamatergic neuronal populations of the olfactory bulb (OB) (i.e., mitral cells), basolateral amygdala (BLA) (i.e., cortical pyramidal-like neurons), hippocampus (i.e., CA3 pyramidal neurons), and medial prefrontal cortex (mPFC) (i.e., layers V/VI pyramidal neurons) (8). In rodents, these corticolimbic structures regulate emotional behavioral responses, including aggression, through the action of neurons projecting from the OB, mPFC, and hippocampus to the BLA, central, and medial amygdala.…”

Social Isolation During Postweaning Development Causes Hypoactivity of Neurons in the Medial Nucleus of the Male Rat Amygdala

“…Social isolation can stunt the maturation of other brain regions (Sanchez et al, 1995;Helmeke et al, 2001;Lapiz et al, 2003;Gos et al, 2006;Agis-Balboa et al, 2007;Gilabert-Juan et al, 2012;Makinodan et al, 2012). The MeA abnormalities caused by social isolation may also be due to a stunting of maturation, such that MeA neurons display an immature phenotype.…”

“…Rearing of rats in social isolation after weaning leads to a range of abnormal social behaviors including increased aggression, abnormal interactions with novel rodents, abnormal sexual behavior, and impaired social learning (Gerall et al, 1967;Meaney and Stewart, 1981;Hol et al, 1999;van den Berg et al, 1999a;Cooke et al, 2000;Von Frijtag et al, 2002;Melo et al, 2006;Agis-Balboa et al, 2007;Toth et al, 2012;Yusufishaq and Rosenkranz, 2013). Furthermore, postweaning social isolation causes reduced MeA volume (Cooke et al, 2000), reduced MeA neurogenesis (Lieberwirth et al, 2012), increased neural cell adhesion molecule (Gilabert-Juan et al, 2012), and morphological changes of MeA neurons (Ichikawa et al, 1993).…”