GABA_A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons

In the adult mammalian brain, GABA_A receptors (GABA_ARs) are responsible for the predominant forms of synaptic inhibition, but these receptors can excite neurons when the chloride equilibrium potential (E_Cl) is depolarized. In many mature neurons, GABA_ARs are found on presynaptic terminals where they exert depolarizing effects. To understand whether excitatory GABA action affects axonal function, we used transverse cerebellar slices to measure the effects of photolysis of caged GABA on the initiation and propagation of compound parallel fiber (PF) action potentials (APs). Photolysis of caged GABA increased the amplitude and conduction velocity of PF APs; GABA reuptake blockers and a positive modulator of GABA_ARs enhanced these effects. In contrast, a modulator selective for δ-subunit-containing GABA_ARs did not enhance these effects and responsiveness remained in δ^-/- mice, arguing that δ-subunit-containing GABA_ARs are not required. Synaptically released GABA also increased PF excitability, indicating that the mechanism is engaged by physiological signals. A Hodgkin-Huxley-style compartmental model of the PF axon and granule cell body was constructed, and this model recapitulated the GABA-dependent decrease in AP threshold and the increase in conduction velocity, features that were sensitive to E_Cl and to the voltage dependence of sodium channel inactivation. The model also predicts that axonal GABA_ARs could affect orthodromic spike initiation. We conclude that GABA acting on cerebellar PFs facilitates both spike generation and propagation, allowing axons of granule cells to passively integrate signals from inhibitory interneurons and influence information flow in the input layer to the cerebellar cortex. © 2012 the American Physiological Society.