Ovariectomy reduces cholinergic modulation of excitatory synaptic transmission in the rat entorhinal cortex

Abstract

Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17β-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17β-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 μM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17β-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17β-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.

Effects of Regular Exercise and Intermittent Fasting on Neurotransmitters, Inflammation, Oxidative Stress, and Brain-Derived Neurotrophic Factor in Cortex of Ovariectomized Rats

“…We have discovered that ovariectomy causes decreases in cortical acetylcholinesterase (AChE). Our findings are consistent with those of Batallán Burrowes et al [70], who discovered that OVX decreased the levels of M1 and AChE receptor protein in the medial and lateral entorhinal cortex and that continuous replenishment of 17β-estradiol mitigated these reductions. Moreover, the disruption of central cholinergic neuronal pathways in the basal forebrain is strongly linked to the estrogen deficiency that led to Aβ accumulation.…”

“…According to Monteleone et al [69], all of these alterations result in neuroanatomical alterations in brain regions related to anxiety and depression, including the raphe nucleus, hippocampus, and cerebral cortex. Moreover, it is believed that decreases in estrogens after ovariectomy affect cognitive functions partly through diminishing the activity of cholinergic afferents to the hippocampus [70,71], but decreased cholinergic input to the entorhinal cortex is also probably going to have an effect. We have discovered that ovariectomy causes decreases in cortical acetylcholinesterase (AChE).…”

Association of biological sex with clinical outcomes and biomarkers of Alzheimer’s disease in adults with Down syndrome

“… 69 , 70 Oestrogens (the primary female sex hormones) act through receptors that are also present in the brain 71 and have been reported to reduce Aβ toxicity by stimulating the metabolism of APP, inhibiting the aggregation of Aβ, or stimulating its degradation. 72‐74 Besides modulating amyloid pathology, oestradiol (the primary form of oestrogen) is known to promote cholinergic activity 75 as well as to enhance memory consolidation and synaptic plasticity in transgenic mice. 76 Interestingly, this protective effect is not seen in mice who are APOE ɛ4 carriers.…”

Sex and menstrual cycle influence human spatial navigation strategies and performance

“…E2 may also affect entorhinal cortex structure and function. For example, ovariectomy in rodents leads to disruptions in cholinergic function of the entorhinal cortex 27 . The behavioral effects of such neural changes on navigation have been rarely studied.…”

“… Anterior hippocampus- and entorhinal cortex-dependent face recognition (Cambridge Face Memory Test 68 ): Aligning with presumed increased anterior hippocampus volume, PO will show better performance than EF + ML and men. Entorhinal cortex-dependent path integration (Path and Location Integration Tasks 69 ): If entorhinal cortex function is positively affected by E2 27 , PO will show better performance than EF + ML and men. Exploratory analyses controlling for videogame experience were conducted to investigate whether a gendered factor, videogame experience, influenced sex- and menstrual cycle-dependent effects.…”