Adenosinergic Modulation of Layer 6 Microcircuitry in the Medial Prefrontal Cortex Is Specific to Presynaptic Cell...

Adenosinergic modulation in the PFC is recognized for its involvement in various behavioral aspects including sleep homoeostasis, decision-making, spatial working memory and anxiety. While the principal cells of layer 6 (L6) exhibit a significant morphological diversity, the detailed cell-specific regulatory mechanisms of adenosine in L6 remain unexplored. Here, we quantitatively analyzed the morphological and electrophysiological parameters of L6 neurons in the rat medial prefrontal cortex (mPFC) using whole-cell recordings combined with morphological reconstructions. We were able to identify two different morphological categories of excitatory neurons in the mPFC of both juvenile and young adult rats with both sexes. These categories were characterized by a leading dendrite that was oriented either upright (toward the pial surface) or inverted (toward the white matter). These two excitatory neuron subtypes exhibited different electrophysiological and synaptic properties. Adenosine at a concentration of 30 µM indiscriminately suppressed connections with either an upright or an inverted presynaptic excitatory neuron. However, using lower concentrations of adenosine (10 µM) revealed that synapses originating from L6 upright neurons have a higher sensitivity to adenosine-induced inhibition of synaptic release. Adenosine receptor activation causes a reduction in the probability of presynaptic neurotransmitter release that could be abolished by specifically blocking A₁ adenosine receptors (A₁ARs) using 8-cyclopentyltheophylline (CPT). Our results demonstrate a differential expression level of A₁ARs at presynaptic sites of two functionally and morphologically distinct subpopulations of L6 principal neurons, suggesting the intricate functional role of adenosine in neuronal signaling in the brain.