Glud1-flox Mouse

GluD1, an ionotropic glutamate receptor family member, binds GABA, challenging the classical dichotomy between glutamatergic and GABAergic receptors. It's present at both excitatory and inhibitory synapses and plays a role in non-ionotropic enhancement of GABAergic synaptic currents in the adult mouse hippocampus through trans-synaptic anchoring [1]. GluD1 also forms trans-synaptic adhesion complexes with secreted cerebellins and presynaptic neurexins, controlling glutamate receptor activity without affecting synapse numbers [4].

GluD1-KO mice show impaired fear memory, decreased sociability, and enhanced depressive-like behavior, suggesting its critical roles in these processes [2]. In muscle stem cells (MuSCs), deletion of Glud1 leads to precocious differentiation and fusion, loss of self-renewal, due to mitochondrial glutamate accumulation and inhibition of the malate-aspartate shuttle [3]. In clear cell renal cell carcinoma (ccRCC), GLUD1 overexpression suppresses cell proliferation, colony formation and migration by inhibiting the PI3K/Akt/mTOR pathway [5]. In hepatocellular carcinoma (HCC), GLUD1 silencing promotes cell growth and migration, while overexpression inhibits HCC progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis [6,7]. Macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischaemia or ageing [8].

In conclusion, GluD1 plays essential roles in neural plasticity, behavior, muscle stem cell fate, and tumorigenesis. Gene-knockout mouse models have been crucial in revealing these functions, contributing to our understanding of related disease mechanisms such as in mental disorders, muscle regeneration-related conditions, and various cancers.