Endocannabinoid signalling is required for estrogen-dependent modulation of inhibitory transmission.

ABSTRACT

It has long been known that the classic female estrogen, 17β-estradiol (E2), is produced in multiple brain regions including the hypothalamus, hippocampus, as well as sensory areas such as the auditory and visual cortices (McEwen 2002; Woolley 2007; Jeong et al. 2011; Tremere et al. 2011; Pinaud and Tremere 2012). Importantly, this brain-generated E2, distinct from the gonadal hormone, exerts local effects by acting on estrogen receptors that are also expressed in these diverse brain areas. As such, E2 derived in the brain has been shown to play multiple functional roles ranging from sensory processing, reproductive biology and cognitive processes including those supporting learning and memory formation (McEwen 2002; Woolley 2007; McCarthy 2008; Pinaud and Tremere 2012). Notably, many of E2’s effects on neuronal physiology occur rapidly – on a scale of seconds; such rapidity is achieved by E2’s actions on the intrinsic and synaptic communication between neurons and via non-genomic mechanisms (Woolley 2007; Pinaud and Tremere 2012). The mechanistic bases of these actions are not well understood and vary across brain regions. In a recent article published in Neuron, Huang and Woolley (2012) shed significant light on the mechanisms through which E2 modulates synaptic transmission in the adult hippocampus, a brain structure heavily implicated in learning and memory (Huang and Woolley 2012). Specifically, the authors revealed a complex basis for E2’s suppressive effects on peri-somatic inhibitory neurotransmission for pyramidal cells in the hippocampal CA1 subfield. Surprisingly, the effects of E2 on inhibitory transmission were sex specific, occurring in female, but not male, adult rats despite both being subjected to gonadectomization prior to the experiments. Huang and Woolley used hippocampal slices where recordings were obtained from CA1 pyramidal cells. Bath application of E2 was used to explore its impact on inhibitory neurotransmission. Interestingly, E2 largely suppressed the amplitude of both unitary and compound inhibitory post-synaptic currents (IPSCs), similar to findings obtained in other preparations (Tremere et al. 2009). The authors next demonstrated that such modulatory effects of E2 are mediated by the classic intracellular estrogen receptor α (ERα) given that PPT, a selective ERα agonist, produced effects that were identical to E2 on IPSC amplitude and pairedpulse ratios. No effects were detected for ERβ, as activation of this receptor subtype with a selective agonist (DPN) failed to impact E2-sensitive IPSCs. One of the most interesting twists of the Huang and Woolley studies was the finding that activation of ERα alone was not sufficient to alter inhibitory transmission. On CA1 neurons, suppression of inhibition requires both the actions of type-1 cannabinoid receptors (CB1Rs) and metabotropic glutamate receptors, in particular mGluR1-containing receptors (Katona et al. 1999). Huang and Woolley showed, however, that in the absence of functional CB1R signalling, E2 is incapable of suppressing inhibitory responses, thereby establishing that E2’s actions at CA1 neurons depend on cannabinoid signalling through CB1Rs. Specifically, when CB1Rs were blocked, neither E2 nor the ERα agonist affected inhibitory neurotransmission. The reverse scenario was also true activation of CB1Rs with a selective agonist could largely capture the E2-mediated suppression of IPSCs and paired pulse ratios. In light of the original discovery that E2’s effects were strongly connected to CB1R signalling, a deeper appreciation of this relationship was sought after by the authors. To this end, Huang and Woolley determined how manipulation of either endocannabinoid, 2-arachidonoylglycerol (2-AG) or