ReviewGPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performance
Research Highlights
► GPR30 is expressed in brain regions important for learning, memory, and attention. ► GPR30 is expressed by the vast majority of cholinergic neurons in the basal forebrain. ► GPR30 may be a regulator of basal forebrain cholinergic function. ► GPR30 may be an important therapeutic target to restore estrogen effects on cognition.
Section snippets
Estrogen effects on cognition
Animal studies show that estrogens have many beneficial effects on the brain, including reducing neuronal loss following cardiac arrest and stroke (Suzuki et al., 2006), increasing neuronal connectivity (Spencer et al., 2008), improving cognitive performance (Daniel, 2006), and preventing or slowing age-related cognitive decline (Frick, 2009, Gibbs and Gabor, 2003). Young adult ovariectomized rats and mice treated with estradiol perform better on learning and memory tasks such as T-maze and
The cholinergic hypothesis
The reasons for the loss of estrogen effect with age and time following menopause have yet to be explained. Cholinergic inputs to the hippocampus and cortex are known to play an important role in mediating effects of estrogens on cognitive performance (reviewed in Gibbs, 2010). Therefore, it is possible that deficits in cholinergic function that occur with age and time following menopause are responsible, at least in part, for the loss of estrogen effect.
Cholinergic neurons in the medial septum
Mechanisms of estrogen effects on cholinergic function
The mechanism(s) by which estradiol increases the functionality of BFCNs is unclear. Two nuclear estrogen receptors (ERs) have been identified, ERα and ERβ (Toran-Allerand, 2004). These nuclear receptors regulate gene transcription but are also capable of activating second messenger signaling pathways such as mitogen-activated protein kinases (MAPK), calcium/calmodulin-dependent protein kinases (CamKII), and cAMP response element-binding proteins (CREB) (Manavathi and Kumar, 2006, McEwen, 2002
GPR30 is expressed by cholinergic neurons in the basal forebrain
Our initial studies evaluated GPR30 expression in the rat forebrain and tested whether GPR30 is expressed by specific cholinergic cell groups. GPR30-like immunoreactivity was detected in many regions of the forebrain including hippocampal pyramidal cells, pyramidal neurons in frontal cortex, cells in the hypothalamus, as well as regions containing basal forebrain cholinergic cell groups (Hammond et al., 2010) (Fig. 1). Using RT-PCR, we also verified that GPR30 mRNA is detectable in each of
Activation and inhibition of GPR30 affects cholinergic function
To determine whether GPR30 influences basal forebrain cholinergic function, we evaluated whether treating rats with G-1 or G-15 significantly affects ACh release in the hippocampus. In one experiment, ovariectomized (Ovx) rats were treated with G-1, E2, or vehicle using a miniosmotic pump implanted subcutaneously. These pumps deliver continuously at a rate of 12 μL/day, and rats were treated with a dose of 5 μg/day G-1 or E2. Rats also received a guide cannula positioned immediately over the
Effects of G-1 and G-15 on spatial learning
E2 enhances acquisition of a delayed matching-to-position T-maze task by Ovx rats, and cholinergic inputs to the hippocampus are critical for this effect (Gibbs, 2002, Gibbs, 2007). To test whether the effects of GPR30 on cholinergic function are relevant to cognitive performance, we evaluated the effects of G-1 and G-15 on DMP acquisition in comparison with the effects of ovariectomy and E2 replacement. Ovx rats were treated with G-1, E2, or vehicle via miniosmotic pump as described above, and
Summary and conclusions
Human and animal studies support the ‘Window of Opportunity’ hypothesis and show that the effects of estrogen therapy on cognitive performance are due, at least in part, to effects on cholinergic inputs to the hippocampus and cortex. We hypothesize that the loss of estrogen effect with age and time following menopause is due to a reduction in the function of these projections. Our recent findings support the hypothesis that GPR30 plays an important role in mediating the effects of estradiol on
Acknowledgments
I acknowledge Douglas Nelson and Amanda Chipman, whose technical assistance contributed to this work. I also acknowledge the National Institutes of Health and the National Science Foundation, which have funded much of the work described in this review.
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