Lack of GSK3β activation and modulation of synaptic plasticity by dopamine in 5-HT1A-receptor KO mice

- A new link between D2R and 5-HT1AR in regulating the E-I balance and the plasticity.
- Functional 5-HT1ARs are needed to allow the “classic” effect of D2R on plasticity.
- Loss of GSK3β signaling recruitment by D2Rs when 5-HT1ARs are absent.
- Dopamine action could be impaired in human pathologies linked to 5-HT1ARs depletion.

Psychiatric disorders are associated with excitation-inhibition (E-I) balance impairment in the prefrontal cortex. However, how the E-I balance is regulated is poorly known. The E-I balance of neuronal networks is linked to the action of numerous neuromodulators such as dopamine and 5-HT. We investigated the role of D2-receptors in tuning the E-I balance in a mouse model of anxiety, the 5-HT1A-receptor KO mice. We focused on synaptic plasticity of excitation and inhibition on layer 5 pyramidal neurons. We show that D2-receptor activation decreases the excitation and favors HFS-induced LTD of excitatory synapses via the activation of GSK3β. This effect is absent in 5-HT1A-receptor KO mice. Our data show that the fine control of excitatory transmission by GSK3β requires recruitment of D2-receptors and depends on the presence of 5-HT1A-receptors. In psychiatric disorders in which the number of 5-HT1A-receptors decreased, therapies should reconsider how serotonin and dopamine receptors interact and control neuronal network activity.