Afferent-specific modulation of excitatory synaptic transmission by acetylcholine and serotonin in the prelimbic...

Acetylcholine (ACh) and serotonin (5-hydroxytryptamine, or 5-HT) differentially regulate the excitability of pyramidal neurons in the mouse prelimbic (PL) cortex according to their long-distance projections. However, less is known about how these modulators regulate synaptic transmission in cortical circuits. We tested for afferent- and/or target-specific modulation of glutamate release by ACh and 5-HT in two excitatory projections to the PL cortex: commissural (COM) afferents from the contralateral PL cortex and projections from the ipsilateral mediodorsal nucleus (MDN) of the thalamus. Using exvivo optogenetic approaches, we mapped the connectivity and neuromodulation of COM and MDN afferents in layer 5 intratelencephalic (IT) and extratelencephalic (ET) projection neurons. Dual whole-cell recordings in pairs of IT and ET neurons revealed that COM afferents monosynaptically target both IT and ET neurons, but that MDN afferents selectively target IT neurons. Both afferents exhibited similar, and target-independent, short-term synaptic plasticity (paired-pulse facilitation), but were differentially modulated by ACh and 5-HT. COM transmission was suppressed strongly by ACh and moderately by 5-HT, while MDN inputs to IT neurons were largely unaffected by either neuromodulator. Suppression of COM transmission by ACh and 5-HT was mediated by M4 muscarinic receptors and 5-HT_1B receptors, respectively. Chemogenetic inhibition of hM4Di-expressing COM terminals mimicked the suppressive effects of ACh and 5-HT on COM synaptic transmission, whereas chemogenetic activation of hM3Dq-expressing COM afferents had no effect. These data suggest that ACh and 5-HT are similarly selective in regulating COM synaptic transmission in the PL cortex in a target-independent manner.