5-HT(1A) receptors direct the orientation of plasticity in layer 5 pyramidal neurons of the mouse prefrontal cortex.

Several psychiatric disorders involving the prefrontal cortex (PFC) are associated with a dysfunction of 5-HT(1A) receptors (5-HT(1A)R). These receptors, located on interneurons and pyramidal neurons, may influence neuronal excitability through a regulation of the balance between excitation (E) and inhibition (I). Patch-clamp recordings in mouse cortical slices were performed to determine the modulatory role of 5-HT(1A)R on the excitability and the synaptic plasticity of layer 5 pyramidal neurons (L5PyNs) of the PFC. This was done by a comparison of postsynaptic currents evoked by electrical stimulation in layer 2/3 of 5-HT(1A)R-KO and wild-type (WT) mice. We observed that the E-I balance was significantly changed from 20% E-80% I in WT mice to 23% E-77% I in 5-HT(1A)R-KO mice, demonstrating that 5-HT(1A)Rs contribute to the control of the balance between excitation and inhibition. Furthermore, we show that interfering with 5-HT(1A)R reduced the magnitude of the long term potentiation of excitation (eLTP) (induced by high frequency stimulation). In addition, we show that 5-HT(1A)Rs determine the orientation of the synaptic plasticity towards LTP or LTD or no plasticity through the modulation of NMDAR-mediated currents. Our data point out to a unique role of 5-HT(1A) postsynaptic receptors in PFC to adapt the functional plasticity of L5PyNs towards LTP, LTD or no plasticity. This brings a new way to intervene on neuronal networks of the PFC in anxiety disorders and schizophrenia.