Allosteric potentiation of GABA receptor single-channel conductance by netrin-1 during neuronal-excitation-induced inhibitory synaptic homeostasis

As the principal receptor that mediates both synaptic and tonic inhibition of neurons in the brain, the A-type gamma-aminobutyric acid receptor (GABAR) is functionally important for maintaining the balance between neuronal excitation and inhibition. Here, we report the identification of netrin-1 as an endogenous allosteric modulator of GABARs. Following increased neuronal excitability, netrin-1 is secreted and binds to the extracellular domains of GABAR subunits, thereby inducing homeostatic upscaling of GABAR-mediated synaptic efficacy and currents. Surprisingly, this homeostatic plasticity is primarily mediated by increasing GABAR single-channel conductance. Our study reveals an important role of netrin-1 as an endogenous GABAR allosteric modulator in maintaining neuronal excitation-inhibition balance, a fundamental process for brain function and dysfunction.