Age-dependent effects of estradiol on temporal memory: A role for the type 1 cannabinoid receptor?

Psychoneuroendocrinology. 2023 Feb;148:106002. doi: 10.1016/j.psyneuen.2022.106002. Epub 2022 Dec 10.


This study investigated in male mice how age modulates the effects of acute 17β-estradiol (E2) on dorsal CA1 (dCA1)-dependent retention of temporal associations, which are critical for declarative memory. E2 was systemically injected to young (3-4 months old) and aged (22-24 months old) adult mice either (i) 1 h before the acquisition of an auditory trace fear conditioning (TFC) procedure allowing the assessment of temporal memory retention 24 h later or (ii) during in vivo electrophysiological recordings of CA3 to dCA1 synaptic efficacy under anesthesia. In young mice, E2 induced parallel dose-dependent reductions in memory and synaptic efficacy, i.e. an impairment in TFC retention and a long-term (NMDA receptor-dependent) depression of dCA1 synaptic efficacy as assessed by field excitatory postsynaptic potentials. In contrast, E2 tended to improved TFC retention whilst failing to change synaptic efficacy in aged mice. Age-dependent effects of E2 treatment were confirmed by immunohistochemical analyses of TFC acquisition-elicited dCA1 Fos activation. Thus, such an activation was respectively reduced and enhanced in young and aged E2-treated mice, compared to vehicle treatments. Hippocampal mRNA expression of estrogen receptors by RT-PCR analyses revealed an age-related increase in each receptor mRNA expression. In keeping with the key role of the endocannabinoid system in memory processes and CA3 to dCA1 synaptic plasticity, we next examined the role of cannabinoid type 1 receptors (CB1-R) in the aforementioned age-dependent effects of E2. Having confirmed that mRNA expression of CB1-R diminishes with age, we then observed that the deleterious effects of E2 on both memory and synaptic efficacy were both prevented by the CB1-R antagonist Rimonabant whilst being absent in CB1-R knock out mice. This study (i) reveals age-dependent effects of acute E2 on temporal memory and CA3 to dCA1 synaptic efficacy and (ii) suggests a key role of CB1-R in mediating E2 deleterious effects in young adulthood. Aging-related reductions in CB1-R might thus underlie E2 paradoxical effects across age.

Keywords: Age; CB1 receptors; Estradiol; Memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Estradiol* / metabolism
  • Estradiol* / pharmacology
  • Hippocampus* / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neuronal Plasticity / physiology
  • RNA, Messenger / metabolism
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Cannabinoid / metabolism


  • Estradiol
  • Receptors, Cannabinoid
  • RNA, Messenger
  • Receptor, Cannabinoid, CB1