Co-transmission of acetylcholine and GABA regulates hippocampal states

Abstract

The basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter. Yet, we find that mouse hippocampal cholinergic terminals invariably establish GABAergic synapses, and their cholinergic vesicles dock at those synapses only. We demonstrate that these synapses do not co-release but co-transmit GABA and acetylcholine via different vesicles, whose release is triggered by distinct calcium channels. This co-transmission evokes composite postsynaptic potentials, which are mutually cross-regulated by presynaptic autoreceptors. Although postsynaptic cholinergic receptor distribution cannot be investigated, their response latencies suggest a focal, intra- and/or peri-synaptic localisation, while GABAA receptors are detected intra-synaptically. The GABAergic component alone effectively suppresses hippocampal sharp wave-ripples and epileptiform activity. Therefore, the differentially regulated GABAergic and cholinergic co-transmission suggests a hitherto unrecognised level of control over cortical states. This novel model of hippocampal cholinergic neurotransmission may lead to alternative pharmacotherapies after cholinergic deinnervation seen in neurodegenerative disorders.

Target-specific co-transmission of acetylcholine and GABA from a subset of cortical VIP+ interneurons

“…A similar level of regulation can be observed in dopaminergic neurons which spatially segregate co-release of glutamate and dopamine in different brain regions (Mingote et al, 2015;Stuber et al, 2010), and whose individual axons segregate terminals that release dopamine or glutamate (Zhang et al, 2015). Similar differentiation of neurotransmitter release has been reported elsewhere in the cholinergic system, specifically in Globus Pallidus externus projections to the cortex (Saunders et al, 2015b) and in hippocampus-projecting septal cholinergic neurons that release ACh and GABA from different synaptic vesicles (Takács et al, 2018). The possibility for separable release of multiple neurotransmitters adds another level of complexity to our understanding of how neurons communicate.…”

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

“…Recordings from interneurons located in stratum oriens revealed fast synaptic responses to light stimulation mediated by nicotinic receptors (Figure 1D) consistent with activation of cholinergic axons and endogenous release of acetylcholine (Leao et al, 2012). In these recordings and further recordings from CA1 pyramidal cells we saw no inhibitory postsynaptic currents that might be caused by light-evoked co-release of GABA or glutamate from either local or long-range ChAT expressing neurons (Figure 1E) (Takacs et al, 2018; Yi et al, 2015).…”

Rapid ‘multi-directed’ cholinergic transmission at central synapses

“…Electron microscopy studies have not provided a consensus regarding the extent to which cholinergic terminals form well-defined synaptic structures 1,2,18,21,22 . What complicates these results is the recent realization that many cholinergic neurons also release a second fast neurotransmitter (GABA [22][23][24][25] or glutamate 19,26 ), often from the same terminal varicosities 19,22,27 , making it difficult to determine the ultra-structural elements that are associated with cholinergic transmission. Results from functional studies also offer a limited view, as they lack the spatiotemporal resolution required to detect synaptic ACh signals (reviewed by 1,2 ).…”

“…Results from functional studies also offer a limited view, as they lack the spatiotemporal resolution required to detect synaptic ACh signals (reviewed by 1,2 ). Even 'phasic' postsynaptic cholinergic responses revealed in electrophysiological studies are relatively slow compared to transmission at conventional glutamatergic/GABAergic synapses 7,22,23,25,28 (Fig. 1b; Extended Data Fig 1); and rarely associated with spontaneous 'miniature' events 9,12 , the standard defining feature of a chemical synapse 29 .…”

“…As with many cholinergic synapses elsewhere in the CNS 17,18,22 , putative secondary peripheral contacts made by starburst wraparounds were devoid of pre-or postsynaptic specializations, making them difficult to verify by anatomy alone (Fig 3d). It is only in the context of our electrophysiological data showing rapid synchronous cholinergic sEPSCs that we can show that transmission likely occurs at such 'tripartite complexes' (i.e., varicosity and two DSGC dendrites; Fig 3d).…”