Abstract
Distinct from ovarian estradiol, the steroid hormone 17ß-estradiol (E2) is produced in the brain and is involved in numerous functions, particularly acting as a neurosteroid. However, the physiological role of E2 and the mechanism of its effects are not well known. In hippocampal slices, 17ß-estradiol has been found to cause a modest increase in fast glutamatergic transmission; because some of these effects are rapid and acute, they might be mediated by membrane-associated receptors via nongenomic action. Moreover, activation of membrane estrogen receptors can rapidly modulate neuron function in a sex-specific manner. To further investigate the neurological role of E2, we examined the effect of E2, as an estrogen receptor (ER) agonist, on synaptic transmission in slices of the prefrontal cortex (PFC) and hippocampus in both male and female mice. Whole-cell recordings of spontaneous excitatory postsynaptic currents (sEPSC) in the PFC showed that E2 acts as a neuromodulator in glutamatergic transmission in the PFC in both sexes, but often in a cell-specific manner. The sEPSC amplitude and/or frequency responded to E2 in three ways, namely by significantly increasing, decreasing or having no response. Additional experiments using an agonist selective for ERß, diarylpropionitrile (DPN) showed that in males the sEPSC and spontaneous inhibitory postsynaptic currents sIPSC responses were similar to their E2 responses, but in females the estrogen receptor ß (ERß) agonist DPN did not influence excitatory transmission in the PFC. In contrast, in the hippocampus of both sexes E2 potentiated the gluatmatergic synaptic transmission in a subset of hippocampal cells. These data indicate that activation of E2 targeting probably a estrogen subtypes or different downstream signaling affect synaptic transmission in the brain PFC and hippocampus between males versus females mice.
Highlights
This is evidenced by the fact that many brain disorders vary in males and females. Most such previous studies involved only males, as it was assumed that female brains are more variable [20]. We examined both male and female mice and report sex differences in the regulation of excitatory synapses, GABAergic inhibition in the hippocampus, and activation of estrogen receptor ß (ERß)-mediated synaptic activity in the prefrontal cortex (PFC)
All recordings were measured in pyramidal neurons in the PFC by whole-cell recording
These recordings showed that the spontaneous excitatory postsynaptic currents (sEPSC) amplitude responded to E2 in different cells
Summary
The classic mechanisms of estrogen, usually in the form of estradiol, involve activating the nuclear receptors estrogen receptor alpha (ERα) and beta (ERß), which subsequently affect the regulation of gene expression, neuroprotection, and neural growth [1,2]. Early experiments have shown that estrogens can acutely affect synaptic responses via nongenomic actions, and these rapid effects are thought to result from the activity of membrane-associated estrogen receptors upon activation by selective receptor agonists [3,4,5]. The neurosteroid 17ß-estradiol (ERß) was found to be produced at high levels within the brain of both males and females. Previous studies have shown that classic estrogen receptor proteins are expressed in the nucleus and at extranuclear sites, including at synapses [6]
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