|dc.description.abstracteng||Aberrant endocannabinoid (eCB) signaling has been implicated in the pathophysiology of different stress-related psychiatric diseases, such as schizophrenia, depression, and anxiety disorders. Such eCB signaling is triggered in postsynaptic neurons and serves to transiently suppress presynaptic neurotransmitter release by activating presynaptic cannabinoid type-1 (CB1) receptors. CB1 receptors are most abundantly expressed in a subpopulation of cortical GABAergic interneurons (INs), which serve to fine-tune cortical information flow by exerting inhibitory control over excitatory networks. Thus, CB1 receptor-expressing (CB1+) INs may represent a substrate linking changes in eCB signaling with stress-induced disease states. However, their function is only poorly understood.
I therefore characterized the properties of CB1+ INs in neocortex and compared them with parvalbumin-expressing (PV+) INs, a well-characterized IN type with an established role in network refinement. To this end, I used a combination of fluorescent imaging, patch-clamp electrophysiology, and pharmacology in double reporter mice, in which CB1+ and PV+ INs are genetically labeled with tdTomato and YFP, respectively. I found that cortical hierarchy strongly shaped the expression of inhibitory circuit motifs made by the two IN types. Specifically, CB1+ INs were considerably less abundant and made considerably fewer GABAergic synapses onto glutamatergic pyramidal neurons compared with PV+ INs in the primary somatosensory cortex, a representative cortical region for primary sensory processing. In contrast, the abundance and inhibitory connectivity was largely balanced between the two IN types in the prefrontal cortex, a higher-order associative cortical structure that serves an important function in cognitive control and stress regulation.
I further characterized the inhibitory circuit properties of the two IN types in the prefrontal cortex across development and assessed their vulnerability towards glucocorticoid-mediated developmental stress. To this end, mice were chronically treated with the stress hormone corticosterone during adolescence, a developmental period of heightened stress vulnerability. I found that GABAergic synapses made by the two IN types onto prefrontal pyramidal neurons reached functional maturity early, before the onset of the adolescent phase. Only their glutamatergic inputs seemed to undergo some form of synapse pruning during adolescence, but these developmental changes were mostly restricted to PV+ INs. Remarkably, GABAergic synapses made by both prefrontal PV+ and CB1+ INs were highly resistant to chronic corticosterone treatment during adolescence, despite inducing a prominent stress- and anxiety-related phenotype. Indeed, basal synaptic transmission was completely preserved at both types of synapses in mice chronically treated with corticosterone. However, GABAergic synapses made by CB1+ INs displayed a deficiency in depolarization-induced suppression of synaptic inhibition, an eCB-dependent form of short-term synaptic plasticity. These results thus indicate a specific corticosterone-induced deficit in eCB-mediated regulation of synaptic transmission at these synapses.
Together, these findings suggest an important role of cortical hierarchy in shaping inhibitory circuit motifs and point to an increased importance of CB1+ INs in regulating excitatory network activity in higher-order cortical structures, such as the prefrontal cortex. Moreover, my results highlight a specific dysfunction in eCB-dependent plasticity at synapses of prefrontal CB1+ INs following chronic glucocorticoid exposure. Thus, CB1+ INs might represent a promising new target for the study of stress-related psychiatric disorders. Future studies should determine to what extent the observed deficit in eCB-dependent plasticity is causally related to stress-induced disease states.||de