Abstract
Both serotonin (5HT) and stress exert changes in cortical inhibitory tone to shape activity of cortical networks. As astrocytes are also known to affect inhibition through established purinergic pathways, we assessed the role of GABA and purinergic pathways in rapid corticosterone (CORT) and 5HT effects on cortical inhibition. We used a paired-pulse paradigm (P1 & P2) in acutely isolated mouse brain slices to evaluate changes in cortical evoked inhibition. Normally, 5HT decreases amplitude of the first pulse P1, while increasing the amplitude of P2 (increase frequency transmission). Interestingly, it was observed that CORT application decreased P1 and increased P2 similarly to 5HT application. Given that CORT and 5HT are known to modulate inhibition, we applied the GABAA antagonist bicuculline in the presence of both and found the increase in P2 and the P2/P1 was lost, providing evidence for a common mechanism involving GABAA receptor signaling. Additional occlusion experiments (5HT in presence of CORT, and CORT in presence of 5HT) provide further support for a common mechanism. As both 5HT and CORT blocked the increase in P2 and P2/P1 of the other, we suggest 5HT/CORT already occupy the mechanism in which they share to affect cortical inhibition. Using low concentrations of the GAPDH inhibitor iodoacetate, commonly used to selectively disrupt astrocyte metabolism, we found the increase in P2 and P2/P1 was similarly blocked in response to both CORT and 5HT. As astrocyte signaling 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 5HT- or CORT-mediated increases in P2 and P2/P1. Together, these results support the common involvement of GABAergic and purinergic pathways in CORT and 5HT effects that may also involve astrocytes.
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