Monocarboxylate transporters (MCTs) are a conserved family that facilitates the flow of monocarboxylates across membranes. MCTs are often required to adapt monocarboxylate bioavailability to cell requirements, a plasticity crucial in energy-demanding nervous system communication. ln the vertebrate nervous system, the primary communication mode is excitatory glutamatergic neurotransmission. The loss of glutamate homeostasis leads to high glutamate, thus excitotoxicity. Glutamate signaling must therefore be tightly regulated. Understanding the underlying regulatory mechanisms is crucial, as their dysregulation leads to numerous neurological disorders. The postsynaptic density (PSD) represents one of these mechanisms and ensures the rigorous control of glutamatergic neurotransmission. Dynamic glutamate receptor (GluR) adaptations at postsynaptic sites, mediated by the PSD, provide regulated synaptic transmission-dependent responses. However, the proteins contributing to dynamic PSD function, such as the primary neuronal MCT MCT2 remain largely unknown. MCT2 ensures lactate uptake as fuel to sustain glutamatergic neurotransmission in an activity­ dependent manner. Notably, several MCT2 studies suggest its involvement in the PSD and a function as an auxiliary subunit of GluRs. Thus, we hypothesize that a dual role of MCT2 could serve as a link between metabolism and synaptic activity.
Here, we use the Drosophila glutamatergic larval neuromuscular junction (NMJ) to
delineate the role of MCTs at the postsynapse. Glutamatergic neurotransmission drives larval crawling. Using this behavioral readout, we screened for and identified CG8028, a yet uncharacterized Drosophi/a MCT, as a potential ionotropic GluR (iGluR) auxiliary subunit. Muscle-specific knock-down of and mutants homozygous for CG8028 display a crawling phenotype due to low abundant iGluRs at postsynaptic sites. lt is further supported by the robust integration of mouse MCT2 (mMCT2) at PSDs of Drosophi/a NMJs, suggesting that mMCT2/CG8028 regulates postsynaptic iGluR levels. Finally, mMCT2 surface localization in vitro is regulated by phosphorylation of its C-terminal PDZ ligand. Our results provide the first in vivo evidence for a potential non-canonical iGluR auxiliary subunit function of postsynaptic MCTs, which would link metabolic supply to glutamatergic synaptic activity.