title: Activity-dependent serotonergic excitation of callosal projection neurons in the mouse prefrontal cortex.
abstract: Layer 5 pyramidal neurons (L5PNs) in the mouse prefrontal cortex respond to serotonin (5-HT) according to their long-distance axonal projections; 5-HT1A (1A) receptors mediate inhibitory responses in corticopontine (CPn) L5PNs, while 5-HT2A (2A) receptors can enhance action potential (AP) output in callosal/commissural (COM) L5PNs, either directly (in "COM-excited" neurons), or following brief 1A-mediated inhibition (in "COM-biphasic" neurons). Here we compare the impact of 5-HT on the excitability of CPn and COM L5PNs experiencing variable excitatory drive produced by current injection (DC current or simulated synaptic current) or with exogenous glutamate. 5-HT delivered at resting membrane potentials, or paired with subthreshold depolarizing input, hyperpolarized CPn and COM-biphasic L5PNs and failed to promote AP generation in COM-excited L5PNs. Conversely, when paired with suprathreshold excitatory drive generating multiple APs, 5-HT suppressed AP output in CPn L5PNs, enhanced AP generation in COM-excited L5PNs, and generated variable responses in COM-biphasic L5PNs. While COM-excited neurons failed to respond to 5-HT in the presence of a 2A receptor antagonist, 32% of CPn neurons exhibited 2A-dependent excitation following blockade of 1A receptors. The presence of pharmacologically revealed 2A receptors in CPn L5PNs was correlated with the duration of 1A-mediated inhibition, yet biphasic excitatory responses to 5-HT were never observed, even when 5-HT was paired with strong excitatory drive. Our results suggest that 2A receptors selectively amplify the output of COM L5PNs experiencing suprathreshold excitatory drive, while shaping the duration of 1A-mediated inhibition in a subset of CPn L5PNs. Activity-dependent serotonergic excitation of COM L5PNs, combined with 1A-mediated inhibition of CPn and COM-biphasic L5PNs, may facilitate executive function by focusing network activity within cortical circuits subserving the most appropriate behavioral output.
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA ; Program in Experimental and Molecular Medicine, Dartmouth College Hanover, NH, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Stephens
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA ; Program in Experimental and Molecular Medicine, Dartmouth College Hanover, NH, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Avesar
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA ; Program in Experimental and Molecular Medicine, Dartmouth College Hanover, NH, USA.
authors.forename: Allan T
authors.initials: AT
authors.lastname: Gulledge
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D007839:Functional Laterality; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D011149:Pons / Q000166:cytology*; D017397:Prefrontal Cortex / Q000166:cytology*; D011725:Pyridines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D005456:Fluorescent Dyes; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
keywords: 5-HT1A receptor; 5-HT2A receptor; executive function; mouse; prefrontal cortex; pyramidal neuron; serotonin