Finally Urban Ciecko et al asked whether this

Finally, Urban-Ciecko et al. (2018) asked whether this enhancement is specific to the pyramidal to SST neuron synapses or more generally observed in other synapses of the cortical microcircuit. Synapses between pyramidal cells showed no sign of potentiation after either bath application of the cholinergic agonist carbachol or release of endogenous induced pluripotent stem cells by optogenetic activation of cholinergic fibers. Testing the synapse between pyramidal cells and parvalbumin (PV)-expressing interneurons, Urban-Ciecko et al. (2018) noted an interesting discrepancy between bath application of the cholinergic agonist and optogenetically evoked endogenous acetylcholine. While carbachol application potentiated pyramidal to PV synapses, this was not observed using optogenetic activation of cholinergic fibers. The synapse specificity of cholinergic enhancement at the pyramidal-SST connection suggests an intriguing possibility: a triadic synapse with cholinergic presynaptic boutons regulating a glutamatergic synapse onto SST interneurons. Although the anatomical basis of this remains to be determined, Urban-Ciecko et al. (2018) provide compelling evidence that phasic cholinergic activity can reconfigure specific circuit elements, in this case, boosting pyramidal-SST feedback inhibition. This impressive study by Urban-Ciecko et al. (2018) sets the stage for understanding how the phasic release of acetylcholine can reconfigure specific cortical circuits in potentially complex ways. At the circuit level, the feedback inhibition mechanism they have discovered may support desynchronization of cortex (Chen et al., 2015, Eggermann et al., 2014) and the enhancement of cortical neuron tuning. During behavior, reinforcers can drive brief cholinergic bursts and VIP neuron activation, thereby creating a circuit configuration for associative plasticity (Hangya et al., 2015). Although somewhat speculative, these possibilities show that the highly-specific boosting of pyramidal-SST synapses could have important consequences for cortical circuit operation during behavior.
Acknowledgments We would like to thank the National Institutes of Health for support and Elizabeth T. Gibson for help in preparing this manuscript.
Introduction A clear example of these developments can be seen in the field of neuronal nicotinic acetylcholine receptor (nAChR) research. The identification of seventeen genes encoding for these proteins and their wide distribution in the central nervous system not only confirmed the importance of the cholinergic innervation but also that these ligand gated ion channels can be the target for specific drugs. As in the case of “Alice in wonderland” (Fig. 1), having a first description of the genes and the possibility to express these genes in recombinant systems, led the scientific world to “dive into the rabbit hole”. It has been acknowledged since then that while studies of recombinant receptors significantly improved our understanding of nAChR function, advances on the road of drug discovery were slow (Table 1). During a rather long period ranging from the nineties up to the last decade, a continuous flow of novel molecules showing improvement in selectivity for precise nAChR subtypes were identified and followed by encouraging preclinical and early clinical studies for neuropsychiatric disorders (see reviews, [1], [2], [3], [4]). Over the last five to six years, there have been multiple phase II clinical trials (e.g., ispronicline, ABT-418, ABT-089) and one phase III clinical trial at α7 nAChR agonists (encenicline) in Alzheimer’s disease (AD) and/or schizophrenia but, unfortunately, the compounds failed to show sufficient efficacy as pro-cognitive agents or they were discontinued prematurely due to unanticipated side effects [5], [6]. This unfortunate situation is not specific to nAChR ligands and in the case of AD, the failure rate of new chemical entities is greater than 99 percent [7]. Such negative results have resulted in the notable decline in research and development for neuropsychiatric disorders by the pharmaceutical industry [4]. Moreover, the negative results have fueled criticisms of the preclinical research and the argument that there is a significant translational gap between animal studies and human clinical trials [8], [6] (Table 2).