The influence of stress at puberty on mood and learning: Role of the α4βδ GABAA receptor

Abstract

It is well-known that the onset of puberty is associated with changes in mood as well as cognition. Stress can have an impact on these outcomes, which in many cases, can be more influential in females, suggesting that gender differences exist. The adolescent period is a vulnerable time for the onset of certain psychopathologies, including anxiety disorders, depression and eating disorders, which are also more prevalent in females. One factor which may contribute to stress-triggered anxiety at puberty is the GABAA receptor (GABAR), which is known to play a pivotal role in anxiety. Expression of α4βδ GABARs increases on the dendrites of CA1 pyramidal cells at the onset of puberty in the hippocampus, part of the limbic circuitry which governs emotion. This receptor is a sensitive target for the stress steroid THP (3α-OH-5[α]β-pregnan-20-one), which paradoxically reduces inhibition and increases anxiety during the pubertal period (~PND 35–44) of female mice in contrast to its usual effect to enhance inhibition and reduce anxiety. Spatial learning and synaptic plasticity are also adversely impacted at puberty, likely a result of increased expression of α4βδ GABARs on the dendritic spines of CA1 hippocampal pyramidal cells, which are essential for consolidation of memory. This review will focus on the role of these receptors in mediating behavioral changes at puberty. Stress-mediated changes in mood and cognition in early adolescence may have relevance for the expression of psychopathologies in adulthood.

The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders

“…Finally, during puberty neurosteroids have been shown to modulate α 4 βδ GABA A R mediated currents in a polarity dependent way by attenuating hyperpolarizing but not depolarizing responses (Shen et al 2007; Smith 2013). This neurosteroid dependent reduction in inhibition may also contribute to negative mood symptoms in PMS/PMDD (see section IV.…”

“…Puberty is a period commonly associated with changes in mood, such as increased anxiety and mood swings in addition to being a vulnerable period for the generation of affective disorders (for review see (Smith 2013). Levels of steroid hormones fluctuate during puberty yet the effects of these hormonal changes on neuronal and network excitability during puberty is still relatively understudied.…”

“…The principle target of neurosteroids, such as the progesterone metabolite allopregnanolone, is the GABA A receptor (GABA A R) family where they have been shown to have anxiolytic, anti-convulsant, sedative/anesthetic, and analgesic properties ((Belelli et al 2009; Belelli and Lambert 2005). Alterations in the level of steroid hormones, such that occur over the estrous cycle, at puberty, and during pregnancy and the postpartum period, have been implicated in triggering affective disorders, such as premenstrual dysphoric disorder (PMDD), postpartum depression and mood changes associated with puberty (Rapkin and Akopians 2012; Smith 2013) (Brummelte and Galea 2010). This review will highlight the evidence suggesting that neurosteroid-mediated alterations in GABAergic inhibition are associated with affective disorders, whilst highlighting the areas of therapeutic promise.…”

Genes Involved in Long-Term Memory Are Expressed in Testis of Cryptorchid Boys and Respond to GnRHa Treatment

“…BDNF mediates EGR3 -induced GABRA4 regulation in developing neurons [Roberts et al, 2006;Smith, 2013]. Both EGR3 and GABRA4 are involved in memory formation [Roberts et al, 2006;Smith, 2013].…”

“…The EGR3 gene plays essential roles in learning and memory processing, which appear to be partly distinct from the actions of EGR1 [Li et al, 2007]. Both EGR3 and GABRA4 genes are involved in memory formation [Roberts et al, 2006;Smith, 2013].…”