Calretinin⁺-neurons-mediated GABAergic inhibition in mouse prefrontal cortex

The prefrontal cortex (PFC) is a center for executive and cognitive functions. Although many studies have been carried out to elucidate the role of different subtypes of GABAergic neurons in other brain areas, their functional relevance in PFC is still not fully understood. Calretinin⁺-GABAergic neurons are heterogeneous in their morphology and intrinsic properties. Previous studies showed an involvement of CR⁺-GABAergic neurons in the disinhibition of the other GABAergic neurons in neocortex and hippocampus. Furthermore, the loss of CR⁺- and PV⁺-interneurons in human brain has been linked to the vulnerability of the interneurons and to the overall increase in the network excitability associated with mental diseases. In the present study, the intensity of CR⁺-neuropil was higher in layer II/III, whereas the intensity of PV⁺-neuropil was higher in deeper layers within the PFC. In addition, pronounced CR expression was detected in layer II and III of prelimbic and infralimbic cortex whereas they were less abundant in anterior cingulate cortex and motor cortex 2. Our results showed that bipolar CR⁺- neurons in layer V not only feedback inhibited multipolar CR⁺- and other interneurons in layer II/III, but the majority of bipolar CR⁺-neurons in layer II/III also provide long-range forward-inhibition to pyramidal neurons in deeper layers of PFC. Thus, given the importance of the neuronal network of PFC in central control of emotion and cognition and in the pathology of mental diseases, CR⁺-GABAergic neuron-mediated feed-forward and -backward modulation within PFC would differentially modulate the downstream limbic activity and subsequently shape the cognitive and emotional behavior.