Activity‐dependent bidirectional regulation of GABAA receptor channels by the 5‐HT4 receptor‐mediated signalling in rat prefrontal cortical pyramidal neurons

Emerging evidence has implicated a potential role for 5‐HT4 receptors in cognition and anxiolysis. One of the main target structures of 5‐HT4 receptors on ‘cognitive and emotional’ pathways is the prefrontal cortex (PFC). As GABAergic signalling plays a key role in regulating PFC functions, we examined the effect of 5‐HT4 receptors on GABAA receptor channels in PFC pyramidal neurons. Application of 5‐HT4 receptor agonists produced either an enhancement or a reduction of GABA‐evoked currents in PFC neurons, which are both mediated by anchored protein kinase A (PKA). Although PKA phosphorylation of GABAA receptor β3 or β1 subunits leads to current enhancement or reduction respectively in heterologous expression systems, we found that β3 and β1 subunits are co‐expressed in PFC pyramidal neurons. Interestingly, altering PKA activation levels can change the direction of the dual effect, switching enhancement to reduction and vice versa. In addition, increased neuronal activity in PFC slices elevated the PKA activation level, changing the enhancing effect of 5‐HT4 receptors on the amplitude of GABAergic inhibitory postsynaptic currents (IPSCs) to a reduction. These results suggest that 5‐HT4 receptors can modulate GABAergic signalling bidirectionally, depending on the basal PKA activation levels that are determined by neuronal activity. This modulation provides a unique and flexible mechanism for 5‐HT4 receptors to dynamically regulate synaptic transmission and neuronal excitability in the PFC network.

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