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We aimed to determine how 5\u2010HT shapes intrinsic excitability and synaptic transmission in defined neuronal populations of the medial PFC (mPFC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We performed whole\u2010cell recordings from morphologically and electrophysiologically characterised layer 5 (L5) neurons in rat mPFC. Pyramidal neurons were classified into adaptive\u2010spiking high input resistance (AS\n                      <jats:sub>H<\/jats:sub>\n                      ), adaptive\u2010spiking low input resistance (AS\n                      <jats:sub>L<\/jats:sub>\n                      ) and regular\u2010spiking (RS) types; interneurons were categorised as non\u2010fast\u2010spiking (nFS), regular\u2010fast\u2010spiking (rFS) and stuttering\u2010fast\u2010spiking (sFS) interneurons. These cell types exhibited distinct membrane properties, firing patterns and axonal projections. We assessed serotonergic modulation using bath\u2010applied 5\u2010HT and subtype\u2010specific receptor mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      5\u2010HT produced divergent postsynaptic responses across pyramidal neuron subtypes: AS\n                      <jats:sub>H<\/jats:sub>\n                      and RS neurons depolarised via 5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      receptor (5\u2010HT\n                      <jats:sub>2A<\/jats:sub>\n                      R) activation, whereas AS\n                      <jats:sub>L<\/jats:sub>\n                      neurons exhibited 5\u2010HT\n                      <jats:sub>1A<\/jats:sub>\n                      R\u2010mediated hyperpolarisation. Among interneurons, rFS and sFS cells depolarised through ionotropic 5\u2010HT\n                      <jats:sub>3A<\/jats:sub>\n                      Rs, whereas nFS interneurons were largely unaffected. At the synaptic level, 5\u2010HT suppressed excitatory synaptic transmission between pyramidal neurons via presynaptic 5\u2010HT\n                      <jats:sub>1B<\/jats:sub>\n                      Rs. Selective activation of presynaptic 5\u2010HT\n                      <jats:sub>3A<\/jats:sub>\n                      Rs enhanced inhibitory transmission from FS interneurons, whereas the overall effect of 5\u2010HT on inhibitory synapses was suppressive, likely reflecting dominant presynaptic 5\u2010HT\n                      <jats:sub>1B<\/jats:sub>\n                      R\u2010mediated inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Serotonin exerts complex, cell type\u2010specific modulation of mPFC microcircuits through distinct somatodendritic and presynaptic receptor pathways. This balanced and targeted regulation provides a mechanistic basis for serotonergic influence on attention, cognitive flexibility, and emotional regulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70573","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:46:37Z","timestamp":1784011597000},"page":"5832-5853","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Serotonin engages divergent 5\u2010HT receptor pathways for cell type\u2010resolved modulation of prefrontal layer 5 microcircuits"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7908-6967","authenticated-orcid":false,"given":"Ramya","family":"Rama","sequence":"first","affiliation":[{"name":"Research Centre J\u00fclich Institute of Neuroscience and Medicine, INM\u201010 Medicine  J\u00fclich Germany"},{"name":"Department of Neuroanatomy, Institute of Anatomy and 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