Radnikow, G. | Search bioRxiv

bioRxiv2025

Serotonin Engages Divergent 5-HT Receptor Pathways for Cell Type-Resolved Modulation of Prefrontal Layer 5 Microcircuits

Background and PurposeSerotonin (5-HT) is a key neuromodulator in the prefrontal cortex (PFC), yet its cell type-specific effects across excitatory and inhibitory microcircuits remain incompletely understood. We aimed to determine how 5-HT shapes intrinsic excitability and synaptic transmission in defined neuronal populations of the medial PFC (mPFC). Experimental ApproachWe performed whole-cell recordings from morphologically and electrophysiologically characterised layer 5 (L5) neurons in rat mPFC. Pyramidal neurons were classified into adaptive-spiking high input resistance (ASH), adaptive-spiking low input resistance (ASL), and regular-spiking (RS) types; interneurons were categorised as non-fast-spiking (nFS), regular-fast-spiking (rFS), and stuttering-fast-spiking (sFS) interneurons. These cell types exhibited distinct membrane properties, firing patterns, and axonal projections. We assessed serotonergic modulation using bath-applied 5-HT and subtype-specific receptor mechanisms. Key Results5-HT produced divergent postsynaptic responses across pyramidal neuron subtypes: ASH and RS neurons depolarised via 5-HT2A receptor (5-HT2AR) activation, whereas ASL neurons exhibited 5-HT1AR-mediated hyperpolarisation. Among interneurons, rFS and sFS cells depolarised through ionotropic 5-HT3ARs, while nFS interneurons were largely unaffected. At the synaptic level, 5-HT suppressed excitatory synaptic transmission between pyramidal neurons via presynaptic 5-HT1BRs, and conversely enhanced GABAergic transmission from FS interneurons via presynaptic 5-HT3ARs. Conclusions & ImplicationsSerotonin exerts bidirectional, cell type-specific serotonergic modulation of local microcircuits that acts to suppress excitation while facilitating inhibition. This balanced and targeted regulation, arising from distinct distributions of somatodendritic and presynaptic 5-HT receptors, provides a mechanistic basis for serotonergic influence on attention, cognitive flexibility, and emotional regulation.

neuroscience↗

bioRxiv2019

Cell Type-Specific Modulation of Layer 6A Excitatory Microcircuits by Acetylcholine in Rat Barrel Cortex

Acetylcholine (ACh) is known to regulate cortical activity during different behavioral states, e.g. wakefulness and attention. Here we show a differential expression of muscarinic ACh receptors (mAChRs) and nicotinic AChRs (nAChRs) in different layer 6A (L6A) pyramidal cell (PC) types of somatosensory cortex. At low concentrations, ACh induced a persistent hyperpolarization in corticocortical (CC) but a depolarization in corticothalamic (CT) L6A PCs via M4 and M1 mAChRs, respectively. At [~]1 mM ACh depolarized exclusively CT PCs via 4{beta}2 subunit-containing nAChRs without affecting CC PCs. Miniature EPSC frequency in CC PCs was decreased by ACh but increased in CT PCs. In synaptic connections with a presynaptic CC PC, glutamate release was suppressed via M4 mAChR activation but enhanced by nAChRs via 4{beta}2 nAChRs when the presynaptic neuron was a CT PC. Thus, in layer 6A the interaction of mAChRs and nAChRs results in an altered excitability and synaptic release, effectively strengthening corticothalamic output while weakening corticocortical synaptic signaling.

neuroscience↗