We all have those seemingly innocent friends who end up causing trouble when they meet. Now, a study has revealed that astrocytes and neurons – generally the best of buddies – employ an epigenetic mechanism involving histone serotonylation when they get together and “kick up a stink”!
A floral-smelling “bunch” of researchers headed by Benjamin Deneen (Baylor College of Medicine) had sought to explore whether induced neuronal activity stimulated epigenetic/transcriptional responses in their intimately connected neighbor – the astrocyte – to impact behavior. The fragrance-infatuated team used odor-induced neuronal activity in the mouse olfactory bulb as a model system to explore any potential effect on astrocytes and regulation of animal behavior.
Let’s hear from Sardar and colleagues on how epigenetics helps astrocytes and neurons to collaborate and kick up a stink:
- Odor-induced neuronal activation in the mouse olfactory bulb prompts widespread and robust differential gene expression in astrocytes
- Odor-induced neuronal activity alters the composition of Sox9-controlled transcriptional complexes in astrocytes to induce Slc22a3 expression, which encodes a neuromodulator transporter protein that regulates sensory processing in the olfactory bulb
- Defective olfactory bulb circuits and odor processing following region-/cell type-specific deletion of astrocytic Slc22a3 implies that loss of this neuromodulator transporter affects astrocyte-neuron communication
- Slc22a3-less astrocytes also display reductions in morphological complexity, calcium activity, levels of the monoamine neuromodulator serotonin, gamma-aminobutyric acid (GABA)-release (an inhibitory neurotransmitter), and histone serotonlyation coupled with impaired olfactory detection, which suggests an additional chronic, long-term role for Slc22a3 astrocyte function and neural communication
- The neuronal-activity-mediated increase in the level of Slc22a3supports increased transport of serotonin into olfactory bulb astrocytes, which becomes deposited in the epigenome as the histone serotonylation modification
- Increases in histone serotonylation support an increase in the expression of GABA-associated genes to indirectly regulate the astrocytic release of GABA and hence control olfactory behavior
- Reducing histone serotonylation in olfactory bulb astrocytes (through mutant H3.3) downregulates astrocytic GABA-related gene expression and astrocytic GABA release to induce olfactory deficits
Together, this aromatic dish of data highlights how an epigenetic mechanism helps astrocytes to integrate neuronal activity and regulate behavior. Future studies will aim to explain how neuronal activity remodels transcriptional complexes (and the roles of activity-dependent protein interactions in astrocyte-neuron communication), explore which neuromodulatory signaling mechanisms in astrocytes directly regulate neurotransmitter signaling and which pass through an epigenomic intermediatory, and reveal the nature of this latter transcriptional regulation mechanism under different behavioral states.
For more on how histone serotonylation helps neurons and astrocytes to collaborate and kick up a stink, see Science, June 2023.