Chronic Aromatase Inhibition Attenuates Synaptic Plasticity in Ovariectomized Mice

Area of Science:

• Neuroscience
• Endocrinology
• Pharmacology

Background:

• Brain estrogen (17β-estradiol, E2) acts as a neuromodulator, influencing neural plasticity and network excitability.
• Chronic estrogen synthesis inhibition, via aromatase inhibitors like letrozole, is employed in adjuvant breast cancer therapy and may cause cognitive side effects.

Purpose of the Study:

• To investigate the effects of letrozole-induced aromatase inhibition on neural plasticity and cognitive function in a mouse model.
• To determine if letrozole impacts synaptic structure, function, and behavior.

Main Methods:

• Developed a mouse model using letrozole to inhibit aromatase in ovariectomized female mice for up to 3 weeks.
• Utilized two-photon longitudinal in vivo imaging to assess spine density and turnover in neocortical pyramidal cells.
• Measured long-term potentiation (LTP) in somatosensory cortex slices and evaluated performance in the novel object recognition test.

Main Results:

• Letrozole treatment reduced spine turnover in neocortical layer 5 pyramidal cells but did not affect spine density.
• Aromatase inhibition led to reduced LTP in layer 2/3 synapses of the somatosensory cortex, indicating impaired functional plasticity.
• While ovariectomized mice showed deficits in novel object recognition, letrozole treatment surprisingly rescued this cognitive impairment.

Conclusions:

• Aromatase inhibition by letrozole impairs structural and functional neural plasticity in the mouse brain.
• Despite plasticity deficits, letrozole treatment unexpectedly improved cognitive performance in a novel object recognition task.
• These findings highlight a complex interplay between estrogen, neural plasticity, and cognition, with implications for breast cancer therapy side effects.