Corticosterone and serotonin similarly influence GABAergic and purinergic pathways to affect cortical inhibitory networks

Both serotonin (5-HT)and stress exert changes in cortical inhibitory tone to shape the activity of cortical networks. Because astrocytes are also known to affect inhibition through established purinergic pathways, we assessed the role of GABA and purinergic pathways with respect to the effects of rapid corticosterone (CORT) and 5-HT on cortical inhibition. We used a paired-pulse paradigm (P1 and P2) in acutely isolated mouse brain slices to evaluate changes in cortical evoked inhibition. Normally, 5-HT decreases the amplitude of the first pulse P1, whereas it increases the amplitude of P2 (increasing frequency transmission). Interestingly, it was observed that CORT application decreased P1 and increased P2 similar to that of 5-HT application. Given that CORT and 5-HT are known to modulate inhibition, we applied the GABA(A) antagonist bicuculline in the presence of both and found that the increase in P2 and the P2/P1 was lost, providing evidence for a common mechanism involving GABA(A) receptor signalling. Additional occlusion experiments (ie, 5-HT in presence of CORT and CORT in presence of 5-HT) provide further support for a common mechanism. Because both 5-HT and CORT blocked the increase in P2 and P2/P1 with respect to the other, we suggest 5-HT/CORT already utilise the shared mechanism to affect cortical inhibition. Using low concentrations of the GAPDH inhibitor iodoacetate, as commonly used to selectively disrupt astrocyte metabolism, we found that the increase in P2 and P2/P1 was similarly blocked in response to both CORT and 5-HT. Because astrocyte signalling depends in large part on purinergic pathways, the purinergic contribution was assessed using Ab129 (P2Y antagonist) and SCH 58261 (A2A antagonist).Once again, P2Y and A2A receptor blockade similarly disrupted 5-HT- or CORT-mediated increases in P2 and P2/P1. Taken together, these results support the common involvement of GABAergic and purinergic pathways in the effects of CORT and 5-HT that may also involve astrocytes.