Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex.

Serotonin (5-HT) imbalances in the developing prefrontal cortex (PFC) are linked to long-term behavioral deficits. However, the synaptic mechanisms underlying 5-HT-mediated PFC development are unknown. We found that chemogenetic suppression and enhancement of 5-HT release in the PFC during the first two postnatal weeks decreased and increased the density and strength of excitatory spine synapses, respectively, on prefrontal layer 2/3 pyramidal neurons in mice. 5-HT release on single spines induced structural and functional long-term potentiation (LTP), requiring both 5-HT2A and 5-HT7 receptor signals, in a glutamatergic activity-independent manner. Notably, LTP-inducing 5-HT stimuli increased the long-term survival of newly formed spines ( ≥ 6 h) via 5-HT7 Gαs activation. Chronic treatment of mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first two weeks, but not the third week of postnatal development, increased the density and strength of excitatory synapses. The effect of fluoxetine on PFC synaptic alterations in vivo was abolished by 5-HT2A and 5-HT7 receptor antagonists. Our data describe a molecular basis of 5-HT-dependent excitatory synaptic plasticity at the level of single spines in the PFC during early postnatal development.

Fetal cannabidiol (CBD) exposure alters thermal pain sensitivity, problem-solving, and prefrontal cortex excitability.

Thousands of people suffer from nausea with pregnancy each year. Nausea can be alleviated with cannabidiol (CBD), a primary component of cannabis that is widely available. However, it is unknown how fetal CBD exposure affects embryonic development and postnatal outcomes. CBD binds and activates receptors that are expressed in the fetal brain and are important for brain development, including serotonin receptors (5HT1A), voltage-gated potassium (Kv)7 receptors, and the transient potential vanilloid 1 receptor (TRPV1). Excessive activation of each of these receptors can disrupt neurodevelopment. Here, we test the hypothesis that fetal CBD exposure in mice alters offspring neurodevelopment and postnatal behavior. We administered 50 mg/kg CBD in sunflower oil or sunflower oil alone to pregnant mice from embryonic day 5 through birth. We show that fetal CBD exposure sensitizes adult male offspring to thermal pain through TRPV1. We show that fetal CBD exposure decreases problem-solving behaviors in female CBD-exposed offspring. We demonstrate that fetal CBD exposure increases the minimum current required to elicit action potentials and decreases the number of action potentials in female offspring layer 2/3 prefrontal cortex (PFC) pyramidal neurons. Fetal CBD exposure reduces the amplitude of glutamate uncaging-evoked excitatory post-synaptic currents, consistent with CBD-exposed female problem-solving behavior deficits. Combined, these data show that fetal CBD exposure disrupts neurodevelopment and postnatal behavior in a sex specific manner.