Subunit-specific expression and function of AMPA receptors in the mouse locus coeruleus

The locus coeruleus (LC) provides the principal supply of noradrenaline (NA) to the brain, thereby modulating an array of brain functions. The release of NA, and therefore its impact on the brain, is governed by LC neuronal excitability. Glutamatergic axons, from various brain regions, topographically innervate different LC sub-domains and directly alter LC excitability. However, it is currently unclear whether glutamate receptor sub-classes, such as a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, are divergently expressed throughout the LC. Immunohistochemistry and confocal microscopy were used to identify and localise individual GluA subunits in the mouse LC. Whole-cell patch clamp electrophysiology and subunit-preferring ligands were used to assess their impact on LC spontaneous firing rate (FR). GluA1 immunoreactive clusters were associated with puncta immunoreactive for VGLUT2 on somata, and VGLUT1 on distal dendrites. GluA4 was associated with these synaptic markers only in the distal dendrites. No specific signal was detected for the GluA2-3 subunits. The GluA1/2 receptor agonist (S)-CPW 399 increased LC FR, whilst the GluA1/3 receptor antagonist philanthotoxin-74 decreased it. 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), a positive allosteric modulator of GluA3/4 receptors, had no significant effect on spontaneous FR. The data suggest distinct AMPA receptor subunits are targeted to different LC afferent inputs and have contrasting effects on spontaneous neuronal excitability. This precise expression profile could be a mechanism for LC neurons to integrate diverse information contained in various glutamate afferents.