Differential effects of serotonin and nitric oxide on the intrinsic properties and network activity of cortical neurons

Serotonin (5HT) and nitric oxide (NO) are important signalling molecules with roles in behavioural control and various psychological conditions. Various lines of evidence suggest interactions between 5HT and NO signalling, however little is known about their interaction in modulating intrinsic properties of cortical neurons and the effects on the neuronal network activity in the cortex. This project studied the effects of 5HT and NO on cultured neurons isolated from Wistar rat cortices. 5HT and NO produced diverse responses in cortical neurons, reflecting the heterogeneity of cortical neuron types. Neither 5HT nor NO appeared to significantly modulate glutamate induced depolarisations. However, they affected the number of APs elicited by the glutamate response, hinting at the possible modulation of intrinsic membrane properties. Subsequently, k-Means clustering based on 10 electrophysiological parameters was used to divide cultured cortical neurons into 10 different cell types with consistent firing properties. 5HT and NO had diverse, cell-type specific effects on neuronal excitability and cellular parameters in these cell types. Furthermore, 5HT and NO showed complex interactions between each other, suggesting modulatory cross-talk. Using ODQ to block soluble guanylate cyclase activity suggests that NO effects are mediated not only by sGC/cGMP signalling, but also S-nitrosylation. Comparing results obtained in cell culture to data from acute cortical slices showed similarities in basic cellular properties. However, 5HT and NO effects on pyramidal cell properties differed markedly between slices and cultures. At the network level, 5HT increased the spontaneous EPSC frequency in pyramidal neurons through 5HT2 receptors, whereas NO had no effect. Interestingly, NO was able to reduce the 5HT induced increase in EPSC frequency when inhibitory synaptic interactions were blocked, possibly by modulating 5HT1 receptor function. The results obtained demonstrate the interaction between 5HT and NO in modulating both intrinsic membrane properties and neocortical network activity.