Localization of Mineralocorticoid Receptors at Mammalian Synapses

Abstract

In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

“…Although GRs are primarily described as nuclear receptors, which require time to translocate from the cytoplasmic compartment to the nucleus to alter gene expression (Beato and SanchezPacheco, 1996), there are several recent studies which indicate that there may be fast-acting non-genomic effects of GRs, as well as for mineralocorticoid receptors (MRs) (for a review, see Groeneweg et al (2011)). Evidence for the existence of GR and MR near the membrane has been verified using synaptosome extracts (Komatsuzaki et al, 2005;Qiu et al, 2010;Wang and Wang, 2009) and using electron microscopy of the neuronal membrane (Johnson et al, 2005;Prager et al, 2010). The presence of GRs near the membrane may account for the rapid behavioral effects seen following both the systemic and intra-CeA administration (30 and 10 min pretreatment, respectively) of mifepristone in this study.…”

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

“…A common finding in previous studies was that gene transcription and protein translation are not required for the rapid actions of CORT on neuronal function (11,12,15). Notwithstanding some exceptions (1,8), the fast neuronal actions of CORT do not appear to be mediated by nuclear MR and GR.…”

Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multi-modal stress

“…Within the amygdala, we found higher levels of Fos expression in the CEA after the multimodal vs restraint stress. The CEA is rich in stress hormones and their receptors, [98][99][100][101] and contributes to processing of stress signals. [102][103][104] Functionally, CEA has been implicated in learning and expression of fear responses, [105][106][107] as well as the expression of stress-induced anxiety behaviors.…”