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Neurons originating from the raphe nuclei of the brain stem are the exclusive source of serotonin (5-HT) to the cortex. Their serotonergic phenotype is specified by the transcriptional regulator Pet-1, which is also necessary for maintaining their neurotransmitter identity across development. Transgenic mice in which Pet-1 is genetically ablated (Pet-1(-/-)) show a dramatic reduction (∼80%) in forebrain 5-HT levels, yet no investigations have been carried out to assess the impact of such severe 5-HT depletion on the function of target cortical neurons. Using whole cell patch-clamp methods, two-dimensional (2D) multielectrode arrays (MEAs), 3D morphological neuronal reconstructions, and animal behavior, we investigated the impact of 5-HT depletion on cortical cell-intrinsic and network excitability. We found significant changes in several parameters of cell-intrinsic excitability in cortical pyramidal cells (PCs) as well as an increase in spontaneous synaptic excitation through 5-HT3 receptors. These changes are associated with increased local network excitability and oscillatory activity in a 5-HT2 receptor-dependent manner, consistent with previously reported hypersensitivity of cortical 5-HT2 receptors. PC morphology was also altered, with a significant reduction in dendritic complexity that may possibly act as a compensatory mechanism for increased excitability. Consistent with this interpretation, when we carried out experiments with convulsant-induced seizures to asses cortical excitability in vivo, we observed no significant differences in seizure parameters between wild-type and Pet-1(-/-) mice. Moreover, MEA recordings of propagating field potentials showed diminished propagation of activity across the cortical sheath. Together these findings reveal novel functional changes in neuronal and cortical excitability in mice lacking Pet-1.

Abnormal cell-intrinsic and network excitability in the neocortex of serotonin-deficient Pet-1 knockout mice