Allosteric potentiation of GABAA 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 (GABA A R) 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 GABA A Rs. Following increased neuronal excitability, netrin-1 is secreted and binds to the extracellular domains of GABA A R subunits, thereby inducing homeostatic upscaling of GABA A R-mediated synaptic efficacy and currents. Surprisingly, this homeostatic plasticity is primarily mediated by increasing GABA A R single-channel conductance. Our study reveals an important role of netrin-1 as an endogenous GABA A R allosteric modulator in maintaining neuronal excitation-inhibition balance, a fundamental process for brain function and dysfunction. [Display omitted] • Endogenous netrin-1 is secreted during neuronal excitation and binds to GABA A Rs • Netrin-1 mediates homeostatic upscaling of the GABA A R synaptic efficacy • Netrin-1 allosterically potentiates GABA A R single-channel conductance Chan et al. reveal an important role of netrin-1 as an endogenous GABA A receptor allosteric modulator in fine-tuning neuronal excitation-inhibition balance through a mechanism of potentiating GABA A receptor single-channel conductance during excitation-induced inhibitory synaptic homeostasis. [ABSTRACT FROM AUTHOR]