Reduced synaptic plasticity and excitatory synapse density contribute to age-related cognitive decline, and constrain recovery of function from injury in adults. A parallel reduction in circulating sex hormones in both sexes, particularly estrogens, exacerbates this decline in synaptic plasticity. Conversely, estrogen therapy in aged members of many species restores synapse density, promotes synaptic plasticity, and improves learning/memory. Importantly, acute estrogen administration can promote rapid synaptogenesis, and these new synapses can be stabilized by activity.

Here I ask if estrogen treatment can promote synaptic plasticity in the primary visual cortex (V1) of aged rats. I demonstrate robust expression of estrogen receptors (ERs) in V1 of adult male and female rats, suggesting an opportunity to enhance plasticity with estrogens. I test this hypothesis following the induction of amblyopia by chronic monocular deprivation (cMD). I show that cMD reduces thalamic innervation from the deprived eye, and increases molecular markers which constrain plasticity, consistent with observations that the deficits induced by cMD are highly resistant to reversal. Surprisingly, cMD did not change markers for excitatory synapses, suggesting a homeostatic increase in synapses serving the non-deprived eye (NDE) to maintain synaptic density within an optimal range. Importantly, visually-evoked potentials (VEPs) induced by repetitive visual stimulation to the deprived eye depress more rapidly than those of the NDE, consistent with cMD inducing an increase in the probability of neurotransmitter release (Pr) at synapses in the cMD pathway.

In contrast, treatment of cMD adults with a single dose of 17α estradiol significantly increased markers for excitatory synapses, and estradiol treatment followed by visual stimulation also increased markers for excitatory synapse activity. Repetitive estradiol treatments increased excitatory synapse markers, but not synaptic activity markers. Furthermore, one dose of estradiol enhanced VEP amplitude following repetitive visual stimulation, however this was observed only in response to stimulation of the NDE. As presynaptic ERs are known to increase Pr at glutamatergic synapses, this suggests that the effects of estradiol are specific to spared synapses where Pr has not been up-regulated by deprivation. Exploiting this selectivity may allow for receptive field remapping of spared inputs around a scotoma or cortical infarct