FBN-ARO-KO mice exhibited a 70-80% decrease in forebrain levels compared to controls.
Depletion of neuron-derived E2 resulted in significant deficits in forebrain spine and synaptic density.
FBN-ARO-KO mice showed impairments in spatial reference memory, recognition memory, and contextual fear memory.
Restoring forebrain E2 levels through administration reversed molecular and behavioral deficits in FBN-ARO-KO mice.
(LTP) induction was normal, but its amplitude was significantly decreased in FBN-ARO-KO hippocampal slices.
Acute E2 treatment fully rescued the LTP defect, indicating its role in synaptic function.
Compromised rapid signaling pathways (AKT, ERK) were observed in the hippocampus and cortex of FBN-ARO-KO mice.
Simplified
(E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70-80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenousE2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore,studies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatmentMechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain.The steroid hormone 17β-estradiol (E2) is well known to be produced in the ovaries in females. Intriguingly, forebrain neurons also express aromatase, the E2 biosynthetic enzyme, but the precise functions of neuron-derived E2 is unclear. Using a novel forebrain-neuron-specific aromatase knock-out mouse model to deplete neuron-derived E2, the current study provides direct genetic evidence of a critical role for neuron-derived E2 in the regulation of rapid AKT-ERK and CREB-BDNF signaling in the mouse forebrain and demonstrates that neuron-derived E2 is essential for normal expression of LTP, synaptic plasticity, and cognitive function in both the male and female brain. These findings suggest that neuron-derived E2 functions as a novel neuromodulator in the forebrain to control synaptic plasticity and cognitive function. in vivo in vitro in vitro SIGNIFICANCE STATEMENT
Key numbers
70-80%
Decrease in Levels
Comparison of levels in FBN-ARO-KO mice vs. FLOX controls.
28.3%
Decrease in Spine Density
Mean spine density decrease in hippocampal CA1 region of male FBN-ARO-KO mice.
94.6%
Rescue of Amplitude
amplitude in FBN-ARO-KO mice after acute treatment.
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