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    • Several studies have recently used optogenetics to

    2024-03-28

    Several studies have recently used optogenetics to selectively activate various cholinergic neurons (Jiang et al., 2014). However, most do not explicitly report direct release of GABA from cholinergic fibers, with the exception of our two studies described above (Saunders et al., 2015a, Saunders et al., 2015b). Some do describe results that are consistent with such a phenomenon but that could also be explained by feed-forward inhibition, such as an increase in inhibitory events and decreases in spiking following photo-activation of striatal cholinergic interneurons (Witten et al., 2010) and suppression of mitral/tufted cell firing in the olfactory bulb following photo-activation of cholinergic fibers from the diagonal band of Broca (Ma and Luo, 2012). Others examined the effects of photo-activation in ways that would not detect GABA release, such as measuring local field potentials or single unit spiking in cortex following activation of BF cyproheptadine hcl sale (Pinto et al., 2013), or recording postsynaptic currents in conditions that would explicitly preclude observing GABAergic responses by including GABA receptor antagonists (Higley et al., 2011, Yang et al., 2014). However, several studies report postsynaptic effects that can be entirely blocked by cholinergic antagonists, arguing against a major role for GABAergic signaling (Nagode et al., 2011, Arroyo et al., 2012, Bennett et al., 2012, Kalmbach et al., 2012, Eggermann et al., 2014, Kalmbach and Waters, 2014, Unal et al., 2015). In these cases, perhaps the specifics of recording configuration, such as recording at or near the reversal potential for GABA receptors, may have prevented the observation of clear GABA-mediated responses. Additionally, the use of transgenic mice that target ChR2 to cholinergic neurons using a bacterical artificial chromosome containing the chat regulatory regions may also interfere with normal synaptic transmission, as these mice lines exhibit several fold increases in expression of VAChT (Kolisnyk et al., 2013). No doubt, future studies that combine optogenetic activation of cholinergic neurons with careful monitoring for GABA-mediated effects will be invaluable for determining when and where the cholinergic system is releasing GABA.
    Sources and targets of GABA/ACh cotransmission To understand the effects on the circuit function of the brain, we must first understand the sources and targets of GABA release from cholinergic neurons. Though the co-labeling of GABAergic markers like VGAT and GAD65 appears widespread throughout cholinergic neurons of the forebrain, including those of the basal forebrain, MSDB, and cortex (Saunders et al., 2015a), it is unclear whether they all, or only some subsets, actually release GABA. It remains possible that expression of VGAT and GAD does not equate to synaptic release of GABA, but instead are expressed for an alternate developmental or evolutionary reasons. Indeed, studies that have attempted to specifically ablate GABAergic projection neurons of MSDB suggest that this may be the case (Pang et al., 2011, Köppen et al., 2013, Roland et al., 2014). The authors used GAT1-SAP, an immunotoxin combining the ribosome-inactivating protein saporin with an antibody against the membrane GABA transporter GAT1, to selectively target and kill GABAergic projection neurons. They report no decrease in the number of cholinergic neurons, suggesting that GABAergic and cholinergic neurons of the MSDB are separate populations. However, this immunotoxin requires expression of GAT1 to be effective, and GAT1 is not an absolute requirement for GABAergic identity. Still, GABA release from cholinergic neurons needs to be confirmed by electrophysiology for each major cholinergic center of the forebrain to determine the extent of GABA/ACh cotransmission. Given our findings of co-expression of mRNA encoding for GAD and ChAT in adult globus pallidus neurons and of GABAergic and cholinergic currents in cortex evoked by ChR2-mediated activation of these neurons (Fig. 1; Saunders et al., 2015b), at least this class of cholinergic neuron mediates a bona fide GABAergic projection as well.