The role of estradiol in astrocyte and neuron communication

Abstract

No longer considered passive players in the brain, astrocytes are now appreciated for their active role in neural communication. The “tripartite synapse” depicts the bidirectional communication between the presynaptic, postsynaptic neuron and the neighboring astrocyte. An important characteristic of this astrocyte-neuron communication is the astrocyte responsiveness to neurotransmitters and the subsequent intracellular calcium mobilization. This intracellular calcium signal triggers the release of gliotransmitters that, activate neuronal receptors, and thereby regulate synaptic function. Most studies on the tripartite synapse have focused on classic neurotransmitters. However, whether other signaling molecules, such as hormones and specifically estrogen, signal to astrocytes and participate in the tripartite synapse function remains largely unknown. To address this knowledge gap, I used an in situ hybridization technique known as RNAscope to examine estrogen receptor (ER) expression in the nucleus accumbens core (NAcC) and CA1 of the hippocampus (Hipp) of adult female and male mice. I then used calcium imaging techniques in hippocampal slices to monitor astrocyte calcium activity in situ and to test whether astrocytes responded to the estrogen 17β-estradiol (E2). Lastly, I used electrophysiology to test whether E2-evoked astrocyte activity could regulate neuronal activity and excitatory synaptic transmission. I describe results in Chapter 3 showing that females and males express ERα and ERβ in CA1 Hipp astrocytes. Females expressed overall more ERs on astrocytes than males. Both females and males predominately expressed ERβ compared with ERα. I was also able to show that E2 increased calcium event frequency in males and females via activation of estrogen receptors ERα and ERβ and the IP3R2 pathway. Lastly, I showed that E2 triggers the release of the gliotransmitters glutamate and ATP/adenosine, which increases the frequency of postsynaptic slow inward currents and depressed excitatory synaptic transmission, respectively. In Chapter 4, I show the results of experiments using the same RNAscope and calcium imaging techniques to test whether E2 signals to nucleus accumbens core astrocytes. I found a small subpopulation of ERs in NAcC astrocytes, with females showing more ER expression than males. Females expressed more ERα and males expressed more ERβ. I used calcium imaging to test whether E2 influenced NAcC astrocyte calcium activity, and I found no changes in event frequency or amplitude. Overall, the functional role of ERs in NAcC astrocytes needs to be explored.