Serotonin regulates electrical coupling via modulation of extrajunctional conductance: H-current

Synaptic strength can be highly variable from animal to animal within a species or over time within an individual. The process of synaptic plasticity induced by neuromodulatory agents might be unpredictable when the underlying circuits subject to modulation are themselves inherently variable. Serotonin (5-hydroxytryptomine; 5HT) and serotonergic signaling pathways are important regulators of animal behavior and are pharmacological targets in a wide range of neurological disorders. We have examined the effect of 5HT on electrical synapses possessing variable coupling strengths. While 5HT decreased electrical coupling at synapses with weak electrical connectivity, synapses with strong electrical coupling were less affected by 5HT treatment, as follows from the equations used for calculating coupling coefficients. The fact that the modulatory effect of 5HT on electrical connections was negatively correlated with the strength of electrical coupling suggests that the degree of electrical coupling within a neural network impacts subsequent neuromodulation of those synapses. Biophysical studies indicated that these effects were primarily due to 5HT-induced modulation of membrane currents that indirectly affect junctional coupling at synaptic contacts. In support of these experimental analyses, we created a simple model of coupled neurons to demonstrate that modulation of electrical coupling could be due solely to 5HT effects on H-channel conductance. Therefore, variability in the strength of electrical coupling in neural circuits can determine the pharmacological effect of this neuromodulatory agent.