Dopaminergic tone inhibits spontaneous glutamate release and augments homeostatic synaptic plasticity

Abstract Dopamine is a monoamine neurotransmitter that regulates neuronal activity and synaptic transmission. While dopaminergic activity is known to suppress action potential-dependent glutamate release in certain brain regions, the modulatory effect of dopaminergic tone on spontaneous glutamate release is unclear. Here, we used primary rat ventral tegmental area-cortex co-cultures to assess how decreased dopaminergic tone affects spontaneous synaptic glutamate release using whole-cell patch-clamp electrophysiology. We found that an acute decrease in dopaminergic tone increases the frequency of spontaneous glutamate release, driven by a surge in basal presynaptic calcium. This presynaptic calcium surge results from disinhibition of voltage-gated calcium channels (VGCCs) due to reduced Gβγ subunit activity downstream of D2 receptor signaling. While acute reduction in dopaminergic tone has robust presynaptic effects, chronic reduction results in homeostatic synaptic plasticity, characterized by postsynaptic insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, a process known as synaptic upscaling. Notably, chronic antagonism of both D1 and D2 receptors using selective antagonists, as well as long-term treatment with first- and second-generation antipsychotics haloperidol, chlorpromazine, olanzapine, clozapine, and aripiprazole, promoted robust synaptic upscaling. These findings reveal a novel mechanism of action for antipsychotic medications and suggest that antipsychotics do not solely act on counteracting hyperdopaminergia, but also tune glutamatergic neurotransmission by activating homeostatic plasticity mechanisms.