Glutamate Delta-1 Receptors Influence Tonic and Synaptic Excitatory Signaling in the Bed Nucleus of the Stria Terminalis

The bed nucleus of the stria terminalis (BNST) is a key integrative hub for stress, reward, and affective processing. As a result, it is of great importance in many neuropsychiatric disorders, including alcohol use disorder (AUD). The BNST is densely innervated by noradrenergic inputs and undergoes significant ethanol-induced alterations in plasticity, such as an α1-adrenergic receptor-dependent long-term depression of excitatory transmission, which involves the endocytosis of calcium-permeable AMPA receptors (CP-AMPARs). In investigating the mechanisms underlying this plasticity, we identified an unexpected tonic excitatory conductance sensitive to NASPM, an antagonist commonly used to block CP-AMPARs, but which also acts on the less studied delta glutamate receptors (δGluRs). Unlike canonical ionotropic glutamate receptors, δGluRs exhibit atypical properties, including a lack of gating by glutamate and constitutive activity. While their synaptic organizational roles are better established, their contribution to intrinsic excitability remains underexplored. The BNST is rich in GluD1, a subtype of these receptors.Using electrophysiological approaches in mice and rhesus macaques, we demonstrate that GluD1 mediates a constitutively active, NASPM-sensitive tonic excitatory conductance in BNST neurons. Blockade of these receptors reduces neuronal excitability and alters synaptic activity. Further, GluD1 function appears to be dynamically regulated by chronic ethanol exposure. These findings identify GluD1 as a previously unrecognized component of BNST intrinsic excitability and highlight its potential involvement in AUD-related neuroadaptations.