Editors’ note: Women run a higher risk of developing chronic pain than do men, and the reasons for this skewed distribution are undoubtedly complex. Two papers described in this news story adapted from the Alzheimer Research Forum show that estrogen modulates inhibitory synaptic transmission and synaptic potentiation in hippocampal circuits in the brains of female, but not male, rodents. The results raise the question of whether similar mechanisms might be at play in other circuits, including those involved in chronic pain.
15 June 2012. Two recent papers focus on the molecular effects of estrogen in the brain, highlighting sex differences in basic synaptic mechanisms. In the June 7 Neuron, researchers led by Catherine Woolley at Northwestern University, Evanston, Illinois, report that estrogen dampens inhibitory synaptic transmission in female, but not male, rats. Likewise, a group led by Gabriele Rune at University Medical Center Hamburg-Eppendorf, Hamburg, Germany, found that a drug that blocks estrogen synthesis in the brain harms synaptic plasticity in female mice more than in male mice. Their results are described in the June 13 Journal of Neuroscience.
“Together, these papers show that sex differences span all the way from the mechanistic level through to the systems level,” Woolley told Alzforum. The data highlight the importance of taking gender differences into account in basic research, she added.
In their Neuron paper, Woolley and first author Guang Zhe Huang demonstrate that estrogen can have sex-specific effects on brain memory mechanisms. Both male and female brains locally produce a key estrogen, 17β-estradiol, which signals rapidly at synapses and can stimulate excitatory transmission (see Woolley, 2007). Huang and Woolley focused instead on the steroid’s effect on inhibitory synapses. When they added estradiol to rat hippocampal slices, the steroid suppressed inhibitory transmission in about 50 percent of CA1 pyramidal neurons in female tissue, but not in male. The authors dissected the pathway using pharmacological blockers of various molecules, finding that estradiol binds to estrogen receptor α (ERα) in the postsynaptic cell. The neurosteroid and its receptor then appear to interact in some fashion with the glutamate receptor mGluR1, causing a signaling cascade that enhances production of the endocannabinoid anandamide. Anandamide released from the post-synapse feeds back to the pre-synapse, discouraging release of the inhibitory neurotransmitter GABA—but only if the pre-synapse contains the CB1 cannabinoid receptor.
Woolley is currently investigating why this interaction only occurs in females, given that male brains contain all the same molecular players. One possibility is that ERα and mGluR1 are less able to make contact in male brains, perhaps due to altered localization, she speculated. She is also intrigued by the presence of an endocannabinoid in this pathway, as these molecules are known to regulate learning and memory as well as emotional states. Women are twice as likely as men to be diagnosed with anxiety and depression, she pointed out. “We think this effect of endocannabinoids might be important in this sex difference.”
Woolley noted that the vast majority of basic neuroscience research is done using male animals, because most scientists assume that brain mechanisms are the same in both sexes, except for regions involved in reproduction. These data show that, “There are at least some fundamental molecular mechanisms in the brain that differ between males and females,” Woolley said. “In order to make science and medicine relevant to everyone, we need to be studying both sexes.”
The paper from the German group adds more support for this idea. Rune and colleagues studied an inhibitor of estradiol synthesis, letrozole, which is frequently prescribed to older women with breast cancer and is suspected of causing memory problems in this population (see Shilling et al., 2001; Dowsett et al., 2005; Shilling et al., 2005). To get at the mechanisms that might underlie this, first author Ricardo Vierk treated male and female mice with the drug for up to seven days, then sacrificed the animals and examined their synapses using hippocampal slice cultures. In some experiments, the authors reversed the order, making slice cultures first and then applying letrozole. In females, letrozole treatment dampened and eventually eliminated long-term potentiation (LTP), a form of synaptic plasticity that is essential for learning and memory, and also led to the loss of synapses and spines in the hippocampus. The effects were much milder in males; they experienced only a 20 percent drop in LTP and lost only thin spines. Though the reason for this gender difference is not yet known, it adds to the evidence for sex-specific mechanisms of synaptic plasticity.