Another open question is whether GABA

Another open question is whether GABA and ACh are released from the same synaptic vesicles, or even the same presynaptic terminals. Multi-transmitter neurons may either function through co-release, in which multiple neurotransmitters are packaged into the same presynaptic terminal and are therefore released simultaneously, or co-transmission, in which the different transmitters are packaged separately and may be differentially released (Vaaga et al., 2014). For the purposes of this review, we have referred to ACh and GABA cotransmission, since preliminary results suggests separate pools of synaptic vesicles (Saunders et al., 2015b), and retinal SACs provide one definitive example of cotransmission (Lee et al., 2010). This latter example also demonstrates how release from separate populations of synaptic vesicles allows for spatial or functional compartmentalization of GABA and ACh release. If GABA and ACh are indeed released from the same neuron but under different conditions or from separate locations, this could explain why cotransmission has been previously overlooked in the literature, as functional identification of cotransmission may be difficult to identify.
Functional consequences of ACh/GABA cotransmission At first glance, release of an excitatory (ACh) and inhibitory (GABA) neurotransmitter by the same AZD2014 would appear to be functionally antagonistic. However, both transmitters could act in parallel, depending on the mode of cotransmission. If both ACh and GABA are released simultaneously onto the same postsynaptic cells, then the GABA may act to restrict or shunt the level of excitation provided by ACh, similar to the corelease of GABA and glutamate in the habenula (Root et al., 2014, Shabel et al., 2014). Along these lines, release of one neurotransmitter may be used to modulate the subsequent release or response to future bouts of stimulation. For example, nAChRs can influence GABA receptors either postsynaptically by decreasing subsequent inhibition through Ca2+-mediate phosphorylation of GABA receptors, or presynaptically by enhancing evoked GABA release (Shrivastava et al., 2011) and presynaptic metabotropic GABA receptors have been shown to inhibit vesicle release in glutamatergic (though as of yet, not cholinergic) synapses (Chalifoux and Carter, 2011). Cotransmission of ACh and GABA might also target different postsynaptic cells, such that GABA inhibits one cell population while ACh excites another. This could be accomplished through postsynaptic cells only expressing one set of receptors, sensitive to either GABA or ACh, or by differentially releasing GABA or ACh in a target-specific manner. In cerebral cortex, excitatory ACh and inhibitory GABA actions can still have the same consequence on overall activity – for example, ACh excites disinhibitory layer 1 interneurons, while GABA directly inhibits interneurons in deeper layers (Letzkus et al., 2011, Pi et al., 2013, Fu et al., 2014, Saunders et al., 2015a). In this case, both transmitters would act to disinhibit and increase cortical activity. In conjunction with possible actions via muscarinic receptors to biochemically enhance plasticity induction, this mechanism may explain many of the proposed effects of cholinergic centers on cerebral cortex.
Conclusion
Acknowledgments The authors thank Yao Chen, Christoph Straub, and Michael Wallace for helpful discussions of the manuscript. We thank the Neurobiology Department and the Neurobiology Imaging Facility for consultation and instrument availability that supported this work. This facility is supported in part by the Neural Imaging Center as part of an NINDS P30 Core Center grant #NS072030. This work was supported by the Jane Coffin Childs Fellowship to AJG and the National Institutes of Health (R01 #NS046579) to BS.
Introduction Billions of years of evolution have led to a staggering array of ion-channel diversity, with different ion-channel types opening and closing in response to a variety of stimuli (Hille, 2001). Opened by the binding of small molecules, ligand-gated ion channels are Nature's ultimate molecular sensors in that they convert chemical signals into electrical impulses. Of all ligand-gated channels, the superfamily of pentameric ligand-gated ion channels (pLGICs) is the largest and most structurally and functionally diverse (Corringer et al., 2012). Formed from five identical or homologous subunits arranged around a central ion-conducting pore, the mammalian family includes both cation and anion-selective channels that are gated by the neurotransmitters acetylcholine, serotonin, γ-aminobutyric acid, and glycine. Although pLGICs are found in virtually all forms of life (Jaiteh et al., 2016), including bacteria (Tasneem et al., 2005), they are most famous for mediating chemical synaptic transmission in the animal nervous system.