Astrocyte beta-adrenergic receptor activity regulates neuronal NMDA receptor signaling

Abstract

Glutamate spillover from the synapse is tightly regulated by astrocytes, limiting the activation of extrasynaptically located NMDA receptors (NMDAR). The processes of astrocytes are dynamic and can affect synaptic physiology. Though norepinephrine (NE) and β-adrenergic receptor (β-AR) activity can modify astrocyte volume, this has yet to be confirmed outside of sensory cortical areas, nor has the effect of noradrenergic signaling on glutamate spillover and neuronal NMDAR activity been explored. We monitored changes to astrocyte process volume in response to noradrenergic agonists in the medial prefrontal cortex of male and female mice. Both NE and the β-AR agonist isoproterenol (ISO) increased process volume by 18%, significantly higher than changes seen in aCSF or when astrocytes had G-protein signaling blocked by GDPβS. We then measured the effect of β-AR signaling on evoked NMDAR currents. While ISO did not affect single stimulus excitatory currents of Layer 5 pyramidal neurons, ISO reduced NMDAR currents evoked by 10 stimuli at 50 Hz, which elicits glutamate spillover, by 18%. After isolating extrasynaptic NMDARs by blocking synaptic NMDARs with the activity-dependent NMDAR blocker MK-801, ISO similarly reduced extrasynaptic NMDAR currents in response to 10 stimuli by 16%. Finally, blocking β-AR signaling in the astrocyte network, by loading them with GDPβS, reversed the ISO effect on 10 stimuli-evoked NMDAR currents. These results demonstrate that astrocyte β-AR activity reduces glutamate spillover and extrasynaptic NMDAR recruitment.