Serotonin guides the way

Some neurological disorders may result from the disruption of particular neurotransmitter systems during development. Even transient disruption during a sensitive period may have lasting effects in the adult. On page 588, Bonnin and colleagues describe how serotonin influences thalamocortical axon guidance in embryonic mice.

Serotonin signaling participates in several developmental programs, including axonal pathfinding. Serotonin receptor subtypes 5-HT_1B and 5-HT_1D overlap in their expression with several axon guidance receptors in the dorsal thalamus. Both of these serotonin receptors act by inhibiting adenylate cyclase, which modulates responsiveness to various axon guidance cues. In the new paper, the authors investigated the mechanism by which serotonin regulates axon guidance. In cell culture, they found that serotonin inhibited adenylate cyclase in dorsal thalamic growth cones, reducing cyclic AMP levels and switching the response to the guidance cue netrin-1 from attraction to repulsion.

The authors then used in utero electroporation to introduce plasmid DNA constructs into progenitor cells destined to populate the dorsal thalamus. These constructs either knocked down or enhanced the expression of the 5-HT_1B and 5-HT_1D receptors. By also electroporating the cells with fluorescent reporters, the authors followed the paths of transfected axons and determined that expression levels of the targeted serotonin receptors directly correlated with the dorsal-ventral axonal patterning and the trajectory of thalamocortical axons originating from the dorsal thalamus. Increasing expression of serotonin receptors (thus reducing cAMP levels) strongly repelled axons from the endogenous netrin-1 gradient on the ventrolateral side of the internal capsule, deflecting them to a more dorsal trajectory. Conversely, reducing expression of serotonin receptors abolished the negative regulation of cAMP levels, thus enhancing the attraction of growth cones to the netrin-1–rich side of the internal capsule, sending these axons more ventrally.

Diminished serotonin signaling during development, by leading to axon positioning defects, could alter the organization and function of brain circuitry, perhaps leading to the eventual manifestation of mental disorders commonly associated with serotonin disruption. Though synaptic serotonin deficits later in life are also likely to contribute to disorders like anxiety and depression, the new study emphasizes another complication of serotonin deficit that could serve as a developmental underpinning for neuropsychiatric diseases.