The Role of Serotonin in Postnatal Plasticity in the Brain
Post by Trisha Vaidyanathan
The takeaway
There is a brief window after birth in which the brain corrects mistakes formed during embryonic development. This window of rewiring is dependent on serotonin and is negatively affected by preterm birth.
What's the science?
Proper wiring of neuronal circuits is critical for brain function and the brain has a remarkable ability to adapt to errors made during development in a process called neuronal plasticity. However, little is known about the timing of this plasticity or what neuronal signals regulate the process. This week in Proceedings of the National Academy of Sciences (PNAS), Sinclair-Wilson and colleagues investigated how the brain corrects for an embryonic developmental error that prevents sensory neurons in the thalamus from reaching their correct targets in the cortex.
How did they do it?
The authors used a powerful genetic mouse model (Ebf1cKO mice) that disrupts the ability of thalamic sensory neurons from finding their appropriate cortical target — a process that would typically occur during embryonic development. As a result of this mutation, somatosensory thalamic neurons invade the visual cortex instead, while visual thalamic neurons never reach their cortical target. Interestingly, it has previously been shown that these embryonic errors in Ebf1cKO mice are corrected postnatally.
To examine appropriate wiring of sensory circuits, the authors used retrograde labeling to quantify how many visual cortex inputs came from the appropriate visual area of the thalamus, rather than the incorrect somatosensory region of the thalamus. In a subset of their experiments, the authors also used in situ hybridization to visualize molecular markers of cortical regions in individual neurons, revealing the sharpness of boundaries around the visual and somatosensory cortex.
First, the authors performed retrograde labeling at successive postnatal developmental ages and identified the specific time window in which the embryonic errors of the Ebf1cKO mice were corrected. Next, the authors induced preterm labor in pregnant Ebf1cKO mice with the drug mifepristone to ask whether preterm birth affected the window of plasticity and ability to correct wiring deficits. Lastly, the authors gave mice pharmacological drugs to either increase or decrease serotonin levels to investigate the hypothesis that serotonin – which prematurely decreases after preterm birth – regulates postnatal plasticity in Ebf1cKO mice.
What did they find?
First, the authors observed that Ebf1cKO embryonic deficits were corrected early in postnatal development, by postnatal day 2. Although sensory thalamic regions in Ebf1cKO mice underwent significant cell death, ultimately the surviving axons were able to find their correct cortical targets and the sensory cortical areas were structurally and functionally intact. This revealed a brief window for postnatal plasticity shortly after birth.
Second, the authors found that inducing preterm birth in Ebf1cKO mice impaired postnatal plasticity. Preterm Ebf1cKO mouse pups still had visual cortex inputs that originated in somatosensory regions of the thalamus, while at the corresponding postnatal day, full-term Ebf1cKO mice had correctly rewired. This demonstrated that preterm birth negatively affects postnatal plasticity and could impact healthy postnatal development.
Lastly, the authors investigated the hypothesis that serotonin, which prematurely decreases in preterm offspring, is necessary for postnatal plasticity. The authors found that daily administration from postnatal day 1 to 3 of a serotonin synthesis inhibitor (parachlorophenylalanine; decreases serotonin levels) impaired plasticity in full-term Ebf1cKO mice, resulting in sensory wiring and cortical boundaries that resembled the preterm Ebf1cKO mice. When the authors administered a selective serotonin reuptake inhibitor (SSRI, fluoxetine) that increases serotonin levels, they were able to rescue the plasticity in preterm Ebf1cKO mice, allowing the sensory thalamic neurons to reach their correct cortical targets and form sharp cortical area boundaries. This revealed that serotonin is a key component of the signaling that underlies postnatal development and the negative impacts of preterm birth.
What's the impact?
This study identified a brief window of plasticity that allows for the correction of errors in embryonic development, and that this window is negatively affected by preterm birth in a serotonin-dependent fashion. Together, this work provides critical insight into the effect of birth timing on brain development and sheds light on potential therapeutic tools that could be used to rescue developmental defects.