Activity-dependent plasticity of presynaptic GABA_B receptors at parallel fiber synapses

Parallel fiber synapses in the cerebellum express a wide range of presynaptic receptors. However, presynaptic receptor expression at individual parallel fiber synapses is quite heterogeneous, suggesting physiological mechanisms regulate presynaptic receptor expression. We investigated changes in presynaptic GABA_B receptors at parallel fiber-stellate cell synapses in acute cerebellar slices from juvenile mice. GABA_B receptor-mediated inhibition of excitatory postsynaptic currents (EPSCs) is remarkably diverse at these synapses, with transmitter release at some synapses inhibited by >50% and little or no inhibition at others. GABA_B receptor-mediated inhibition was significantly reduced following 4 Hz parallel fiber stimulation but not after stimulation at other frequencies. The reduction in GABA_B receptor-mediated inhibition was replicated by bath application of forskolin and blocked by application of a PKA inhibitor, suggesting activation of adenylyl cyclase and PKA are required. Immunolabeling for an extracellular domain of the GABA_B2 subunit revealed reduced surface expression in the molecular layer after exposure to forskolin. GABA_B receptor-mediated inhibition of action potential evoked calcium transients in parallel fiber varicosities was also reduced following bath application of forskolin, confirming presynaptic receptors are responsible for the reduced EPSC inhibition. These data demonstrate that presynaptic GABA_B receptor expression can be a plastic property of synapses, which may compliment other forms of synaptic plasticity. This opens the door to novel forms of receptor plasticity previously confined primarily to postsynaptic receptors.