Circuit-specific enteric glia regulate intestinal motor neurocircuits

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-10, Vol.118 (40), p.1-12
• Main Authors: Ahmadzai, Mohammad M., Seguella, Luisa, Gulbransen, Brian D.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cell Communication; Central nervous system; Cholinergics; Circuits; Colon; Enteric nervous system; Enteric Nervous System - cytology; Enteric Nervous System - physiology; Female; Gastric motility; Gastrointestinal Motility - physiology; Genetic code; Male; Mice; Myenteric plexus; Myenteric Plexus - cytology; Myenteric Plexus - physiology; Nervous system; Neural networks; Neuroglia - cytology; Neuroglia - physiology; Neuronal-glial interactions; Neurons; Neurons - cytology; Signal Transduction; Signaling; Stimulation; Subpopulations
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2025938118

Glia in the central nervous system exert precise spatial and temporal regulation over neural circuitry on a synapse-specific basis, but it is unclear if peripheral glia share this exquisite capacity to sense and modulate circuit activity. In the enteric nervous system (ENS), glia control gastrointestinal motility through bidirectional communication with surrounding neurons. We combined glial chemogenetics with genetically encoded calcium indicators expressed in enteric neurons and glia to study network-level activity in the intact myenteric plexus of the proximal colon. Stimulation of neural fiber tracts projecting in aboral, oral, and circumferential directions activated distinct populations of enteric glia. The majority of glia responded to both oral and aboral stimulation and circumferential pathways, while smaller subpopulations were activated only by ascending and descending pathways. Cholinergic signaling functionally specifies glia to the descending circuitry, and this network plays an important role in repressing the activity of descending neural pathways, with some degree of cross-inhibition imposed upon the ascending pathway. Glial recruitment by purinergic signaling functions to enhance activity within ascending circuit pathways and constrain activity within descending networks. Pharmacological manipulation of glial purinergic and cholinergic signaling differentially altered neuronal responses in these circuits in a sex-dependent manner. Collectively, our findings establish that the balance between purinergic and cholinergic signaling may differentially control specific circuit activity through selective signaling between networks of enteric neurons and glia. Thus, enteric glia regulate the ENS circuitry in a network-specific manner, providing profound insights into the functional breadth and versatility of peripheral glia.