Synaptic Estrogen Receptor-α Levels in Prefrontal Cortex in Female Rhesus Monkeys and Their Correlation with Cognitive Performance

Abstract

In rat hippocampus, estrogen receptor-␣ (ER-␣) can initiate nongenomic signaling mechanisms that modulate synaptic plasticity in response to either circulating or locally synthesized estradiol (E). Here we report quantitative electron microscopic data demonstrating that ER-␣ is present within excitatory synapses in dorsolateral prefrontal cortex (dlPFC) of young and aged ovariectomized female rhesus monkeys with and without E treatment. There were no treatment or age effects on the percentage of excitatory synapses containing ER-␣, nor were there any group differences in distribution of ER-␣ within the synapse. However, the mean size of synapses containing ER-␣ was larger than that of unlabeled excitatory synapses. All monkeys were tested on delayed response (DR), a cognitive test of working memory that requires dlPFC. In young ovariectomized monkeys without E treatment, presynaptic ER-␣ correlated with DR accuracy across memory delays. In aged monkeys that received E treatment, ER-␣ within the postsynaptic density (30 -60 nm from the synaptic membrane) positively correlated with DR performance. Thus, although the lack of group effects suggests that ER-␣ is primarily in synapses that are stable across age and treatment, synaptic abundance of ER-␣ is correlated with individual performance in two key age/treatment groups. These data have important implications for individual differences in the cognitive outcome among menopausal women and promote a focus on cortical estrogen receptors for therapeutic efficacy with respect to cognition.

Sex hormones affect language lateralisation but not cognitive control in normally cycling women

“…This is in line with previous studies showing that estradiol has an enhancing effect on cognitive control in nonlateralised tasks, such as working memory, recognition memory, and response inhibition (Jacobs and D'Esposito, 2011;Keenan et al, 2001). Moreover, this indicates that the prefrontal cortex (PFC) is an important site of estrogen activity in the female brain, as has been proposed by others (Hampson and Morley, 2013;Joffe et al, 2006;Keenan et al, 2001;Wang et al, 2010). In addition, this suggests that cognitive control can be a potential confounder in studies of lateralisation.…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…A detailed review of ERa and ERb structure and function has been published elsewhere (Nilsson et al, 2001). ERa has been observed in the extracellular regions of neurons in the cortex and hippocampus of mouse, rat, rhesus monkey and humans, albeit with a higher expression in the latter region (Milner et al, 2001;Adams et al, 2002;Kritzer, 2002;Mitra et al, 2003;Milner et al, 2005;Gonzalez et al, 2007;Wang et al, 2010). Electron microscopy has located ERa immunoreactivity in dendritic spines, where it associates with spine apparati and/or polyribosomes in rat and rhesus monkey forebrain (Milner et al, 2001;Wang et al, 2010) (Fig.…”

Neuronal and morphological bases of cognitive decline in aged rhesus monkeys

“…The synaptic distribution of estrogen receptor α (ERα) in area 46 has been examined with electron microscopy in the same behaviorally characterized young and aged ovariectomized monkeys (Wang et al 2010). While ERα levels AHP afterhyperpolarization, ACC anterior cingulate cortex, AP action potential, ChAT choline acetyl-transferase, CII Cognitive Impairment Index, CSST conceptual set-shifting task, dlPFC dorsolateral prefrontal cortex, DNMS delayed nonmatching-to-sample, DR delayed response, DRST delayed recognition span test, EPSC excitatory postsynaptic current, IFG inferior frontal gyrus, IPSC inhibitory postsynaptic current, PFC prefrontal cortex, R receptor, RL reversal learning, SFG superior frontal gyrus, vmPFC ventromedial prefrontal cortex Table 2 Anatomical, neuronal, synaptic, and molecular parameters in the monkey hippocampus and related cortical regions in the context of chronological and cognitive aging remain stable across age and hormone treatment groups, the abundance of ERα within the PSD correlates with DR delay performance exclusively in aged monkeys receiving cyclic estradiol (Wang et al 2010). Hence, the cognitive benefits observed in aged monkeys with estradiol may be mediated by the activation of ERα in a synaptic domain coupled to signaling cascades involved in spine/synapse formation and stabilization (Spencer et al 2008).…”