Long-Term Decreases in the Expression of Calcineurin and GABAA Receptors Induced by Early Maternal Separation Are Associated with Increased Anxiety-Like Behavior in Adult Male Rats

Abstract

<b><i>Introduction:</i></b> Early life stress is a well-described risk factor of anxiety disorders in adulthood. Dysfunction in GABA/glutamate receptors and their functional regulator, calcineurin, is linked to anxiety disorders. Here, we investigated the effect of early life stress, such as repeated maternal separation (MS; 3 h per day from postnatal day [P] 2 to 11), on changes in the expression of calcineurin as well as the ionotropic glutamatergic and GABAergic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and GABA<sub>A</sub> receptors in the hippocampus and prefrontal cortex (PFC) of adolescent (P35) and adult (P62) male Wistar rats and their correlations with anxiety-like behavior in adulthood. <b><i>Methods:</i></b> The protein levels were assessed by Western blot analysis. Anxiety-like behavior was measured in the elevated plus maze (EPM) and open field (OF) tests. <b><i>Results:</i></b> MS induced a regional transient decrease of glutamate receptors expression at P35, with decreased NMDA and AMPA receptor levels, respectively, in the hippocampus and PFC, suggesting a possible decrease in excitatory synaptic strength. In contrast to glutamate receptors, MS had long-lasting influence on GABA<sub>A</sub> receptor and calcineurin levels, with reduced expression of GABA<sub>A</sub> receptor and calcineurin in both brain regions at P35 that continued into adulthood. These results were accompanied by increased anxiety behavior in adulthood, shown by lower percentage of number of total entries and time spent in the open arms of the EPM, and by lower time spent and number of entries in the OF central area. <b><i>Conclusions:</i></b> Together, our study suggests that GABA<sub>A</sub> receptors via calcineurin-dependent signaling pathways may play an important role in the expression of stress-induced anxiety-like behavior.

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling

“…Studies have also shown that ELA reduces both allopregnanolone levels and GABA A receptor binding 92 , 93 , suggesting that this endogenous buffering mechanism may be disrupted after MSEW, although previous studies have not considered ELA-induced effects on these measures in the context of estrous stage. Our findings are consistent with the possibility that MSEW-induced increases in avoidance behavior during diestrus are the result of diminished conversion of progesterone to allopregnanolone.…”

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling

“…Studies have also shown that ELA reduces both allopregnanolone levels and GABA A receptor binding (Frye et al, 2006; Mahmoodkhani et al, 2020), suggesting that this endogenous buffering mechanism may be disrupted after MSEW, although previous studies have not considered ELA-induced effects on these measures in the context of estrous stage. Our findings are consistent with the possibility that ELA-induced increases in avoidance behavior during diestrus are the result of diminished conversion of progesterone to allopregnanolone.…”

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling

“…Studies have also shown that ELA reduces both allopregnanolone levels and GABA A receptor binding 82,83 , suggesting that this endogenous buffering mechanism may be disrupted after MSEW, although previous studies have not considered ELA-induced effects on these measures in the context of estrous stage. Our findings are consistent with the possibility that ELA-induced increases in avoidance behavior during diestrus are the result of diminished conversion of progesterone to allopregnanolone.…”