Activation of 5-HT2A receptors by TCB-2 induces recurrent oscillatory burst discharge in layer 5 pyramidal neurons of the mPFC in vitro.

The medial prefrontal cortex (mPFC) is a region of neocortex that plays an integral role in several cognitive processes which are abnormal in schizophrenic patients. As with other cortical regions, large-bodied layer 5 pyramidal neurons serve as the principle subcortical output of microcircuits of the mPFC. The coexpression of both inhibitory serotonin 5-HT1A receptors on the axon initial segments, and excitatory 5-HT2A receptors throughout the somatodendritic compartments, by layer 5 pyramidal neurons allows serotonin to provide potent top-down regulation of input-output relationships within cortical microcircuits. Application of 5-HT2A agonists has previously been shown to enhance synaptic input to layer 5 pyramidal neurons, as well as increase the gain in neuronal firing rate in response to increasing depolarizing current steps. Using whole-cell patch-clamp recordings obtained from layer 5 pyramidal neurons of the mPFC of C57/bl6 mice, the aim of our present study was to investigate the modulation of long-term spike trains by the selective 5-HT2A agonist TCB-2. We found that in the presence of synaptic blockers, TCB-2 induced recurrent oscillatory bursting (ROB) after 15-20 sec of tonic spiking in 7 of the 14 cells. In those seven cells, ROB discharge was accurately predicted by the presence of a voltage sag in response to a hyperpolarizing current injection. This effect was reversed by 5-10 min of drug washout and ROB discharge was inhibited by both synaptic activity and coapplication of the 5-HT2A/2C antagonist ketanserin. While the full implications of this work are not yet understood, it may provide important insight into serotonergic modulation of cortical networks.