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

• Published in: Neuropharmacology Vol. 113; no. Pt A; pp. 124 - 136
• Main Authors: Meunier, C.N.J., Cancela, J.-M., Fossier, P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2017; Elsevier
• Subjects: Animals; Anxiety - metabolism; Anxiety - physiopathology; Cognitive Sciences; Disease Models, Animal; Dopamine; Dopamine Agonists - administration & dosage; Electrophysiology; Excitatory Postsynaptic Potentials - drug effects; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - metabolism; Glycogen Synthase Kinase 3 beta - physiology; Life Sciences; Long-Term Potentiation - drug effects; Long-Term Synaptic Depression - drug effects; Mice; Mice, Knockout; Neurobiology; Neuronal Plasticity - drug effects; Neurons and Cognition; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiology; Psychology and behavior; Pyramidal Cells - drug effects; Pyramidal Cells - physiology; Pyramidal neurons; Quinpirole - administration & dosage; Receptor, Serotonin, 5-HT1A - genetics; Receptor, Serotonin, 5-HT1A - physiology; Receptors, Dopamine D2 - physiology; Receptors, N-Methyl-D-Aspartate - physiology; Serotonin; Electrophysiology; Glycogen synthase kinase 3; Dopamine; Prefrontal cortex; Serotonin; Pyramidal neurons
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.09.025

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. •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.