Pre- and postsynaptic activation of GABA_B receptors modulates principal cell excitation in the piriform cortex

The piriform cortex (PC), like other cortical regions, normally operates in a state of dynamic equilibrium between excitation and inhibition. Here we examined the roles played by pre- and postsynaptic GABA_B receptors in maintaining this equilibrium in the PC. Using whole-cell recordings in brain slices from the anterior PC of mice, we found that synaptic activation of postsynaptic GABA_B receptors hyperpolarized the two major classes of layer 2 principal neurons and reduced the intrinsic electrical excitability of these neurons. Presynaptic GABA_B receptors are expressed on the terminals of associational (intracortical) glutamatergic axons in the PC. Heterosynaptic activation of these receptors reduced excitatory associational inputs onto principal cells. Presynaptic GABA_B receptors are also expressed on the axons of GABAergic interneurons in the PC, and blockade of these autoreceptors enhanced inhibitory inputs onto principal cells. Hence, presynaptic GABA_B autoreceptors produce disinhibition of principal cells. To study the functional consequences of GABA_B activation in vivo, we used 2-photon calcium imaging to simultaneously monitor the activity of ∼200 layer 2 neurons. Superfusion of the GABA_B agonist baclofen reduced spontaneous random firing but also promoted synchronous epileptiform activity. These findings suggest that, while GABA_B activation can dampen excitability by engaging pre- and postsynaptic GABA_B heteroreceptors on glutamatergic neurons, it can also promote excitability by disinhibiting principal cells by activating presynaptic GABA_B autoreceptors on interneurons. Thus, depending on the dynamic balance of hetero- and autoinhibition, GABA_B receptors can function as variable modulators of circuit excitability in the PC.