Activity-dependent serotonergic excitation of callosal projection neurons in the mouse prefrontal cortex

Front Neural Circuits. 2014 Aug 26:8:97. doi: 10.3389/fncir.2014.00097. eCollection 2014.


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.

Keywords: 5-HT1A receptor; 5-HT2A receptor; executive function; mouse; prefrontal cortex; pyramidal neuron; serotonin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Animals
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • Female
  • Fluorescent Dyes / metabolism
  • Functional Laterality
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Neurological
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Piperazines / pharmacology
  • Pons / cytology*
  • Prefrontal Cortex / cytology*
  • Pyridines / pharmacology
  • Reaction Time / drug effects
  • Serotonin / metabolism*
  • Serotonin / pharmacology
  • Serotonin Antagonists / pharmacology


  • Fluorescent Dyes
  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Serotonin
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide