Sex differences in AMPA receptor trafficking proteins

Abstract AMPA receptors are a type of ionotropic glutamate receptor that is important for fast excitatory neurotransmission. healthy brain function. Glutamate signaling is regulated, in part, by the trafficking of glutamate receptors in and out of the synapse. Multiple different trafficking and auxiliary proteins govern this process. Disruptions in this trafficking are linked to various psychiatric diseases, including schizophrenia, major depressive disorder. Glutamate, the primary excitatory neurotransmitter, is crucial for synaptic plasticity and and substance use disorder. Moreover, the incidence and symptomology of these psychiatric diseases impact males and females differently. Despite these epidemiological sex differences, very little research has considered the influence of biological sex on glutamatergic trafficking. Here, we review the current literature on glutamate trafficking proteins for AMPA receptors, most of which have mainly utilized male rodents and cell cultures. The following proteins were explored for AMPA receptors: GRIP, PICK1, NSF, SAP97, AKAP79/150, Protein 4.1 N, and PSD-95. Overall, these studies revealed that our fundamental understanding of glutamate trafficking is based almost completely on studies performed in male animals, and the assumption that the same mechanisms govern AMPAR trafficking in females may not be correct. To fully grasp how these proteins are impacted in disease models, it’s crucial to first understand the baseline sex differences. This is especially important if we want to investigate new research avenues for treating diseases that affect each sex differently.