Study provides evidence that antidepressant use in pregnancy affects child's brain development

By Dr. Liji Thomas, MDReviewed by Danielle Ellis, B.Sc.Feb 19 2024

The prefrontal cortex (PFC) is an important brain region with respect to behavioral regulation. Aberrations in serotonin (5-HT) during early development have been reported to be associated with behavioral dysregulations over the long term, but how this works is still unclear.

A new study published in Nature Communications explored synapse maturation in the PFC of mice when exposed to 5-HT, shedding light on the link between the chemical and future behavioral changes.

Researchers from the University of Colorado Anschutz Medical Campus demonstrated a direct link between antidepressant use during pregnancy, particularly fluoxetine found in medications like Prozac and Sarafem, and altered development of the prefrontal cortex in children, as well as subsequent mental health risks.

Background

The brain has over a billion neurons, with equal numbers of other cells linked in intricate and interwoven networks. These require exquisitely precise chemical regulation to develop correctly so as to provide the substrate for communication between themselves and the formation of neuronal pathways.

5-HT is among the first neurochemicals to be detected, being found at peak levels two years after birth in humans. In mice, it peaks during the first week after birth. This period coincides with the time when excitatory synapses mature following experience-driven activity.

Various causes of alteration in 5-HT are known, including maternal malnutrition, maternal abuse, varying levels of dietary tryptophan (the substrate for 5-HT formation), and the presence of chemicals that regulate the uptake or degradation of 5-HT.

An example of the latter is the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). These can readily cross the placenta or enter breast milk, becoming available to the offspring during a critical period of brain development.

Such imbalances in 5-HT levels at this period have been linked to a higher chance of neurodevelopmental disorders, including autism spectrum disorder (ASD), as well as permanent behavioral changes. The PFC is involved in cognitive processes that facilitate social interaction and is lavishly supplied with neurons that release 5-HT.

Excitatory synapses are fundamental to the formation of neural circuits. They need to mature and stabilize for this to happen, with the primary sites of action of the neurotransmitter released at the synapse being the dendritic spines of the post-synaptic neuron. These bear multiple receptor types for 5-HT, with 5-HT2A and 5-HT7 being especially abundant in early infancy.

When these are activated, excitatory cascades are activated via the coupled Gα_q proteins. Higher levels of 5-HT signaling increase the dendritic spine plasticity. The current study looked at targeted 5-HT signaling at the level of neural circuits and individual excitatory synapses, seeking to identify the mode of regulation. 

What did the study show?

The scientists found that 5-HT is crucial for the normal development of excitatory synapses on the pyramidal neurons within layer 2/3 of the PFC during early development. With 5-HT inhibition, both spine density and maturation were reduced significantly within the PFC, though spine size remained intact. The converse was also true, with increased density, especially of large spines, but with normal size and morphology.

Apart from these anatomical changes, 5-HT signaling causes structural long-term potentiation of dendritic spines on these neurons during this developmental window independent of excitatory stimulation. This effect, namely, the enlargement of small and medium spines, did not appear to depend on the activity of glutamate.

Not only was it specific for the pattern of 5-HT stimulation, but also it was not observed at later stages or in pyramidal neurons. In addition, it occurred only in the presence of post-synaptic 5-HT2A and 5-HT7 signaling. This suggests that the underlying mechanism is 5-HT7 receptor-mediated influx of extracellular calcium ions, leading to 5-HT2A receptor-induced activation of PKC.

Functional long-term potentiation of these receptors was also observed in response to 5-HT release, again via 5-HT2A and 5-HT7 receptor signaling. That is, stronger post-synaptic excitatory currents were measured following 5-HTergic stimulation.

Individual dendritic spines newly formed on these neurons in the PFC were more likely to survive, indicating greater long-term stabilization following Gαs coupled 5-HT7 receptor signaling. This is important as it leads to increased spine density. Again, this effect, linked to long-term potentiation, is independent of glutamate release or structural potentiation and does not appear to occur with 5-HT2A receptor stimulation.

Significantly, early research shows a risk of behavioral deficits and neurodevelopmental disorders with early fluoxetine exposure. In the present study, the use of fluoxetine, an SSRI that increases 5-HT levels in the synaptic cleft in younger but not older pups, led to increased spine density but not spine size. This was mediated by 5-HT2AR and 5-HT7R signaling in the PFC.

What are the implications?

The findings of this study indicate that 5-HT signaling plays a key role in excitatory synapse maturation during early development of the PFC circuits, regulating spine maturation and function. The effect is structural and functional potentiation of excitatory synapses of layer 2/3 pyramidal neurons in the PFC at a specific age and with a specific pattern of stimulation.

The results also suggest a direct effect of 5-HT on maturation rather than via changes in excitability, but further work is required to rule out glutamatergic involvement in synaptic plasticity secondary to 5-HT signaling completely.

The researchers propose that nascent spines are stabilized by 5-HT7 receptor activation via voltage-gated calcium channel opening, leading to the entry of calcium into the neuron. However, as they mature, both 5-HT7 and 5-HT2A receptors lead to synapse maturation via PKC activation, which further enhances extracellular calcium ion influx.

Moreover, 5-HT receptor-mediated synaptic plasticity occurs in the first two weeks in mice. Further research will be required to demonstrate what receptor classes are involved at later stages. Again, increased excitatory post-synaptic current strength without spine size alterations needs to be explained.

These findings may help treat patients who have been exposed to drugs like fluoxetine during early development, as this is a commonly prescribed drug during pregnancy. Moreover, it may be possible to treat individuals with aberrations in 5-HT receptor-mediated plasticity during this key period by selective inhibition of 5-HT receptors in certain brain regions or certain types of neurons.