Neurotransmitter Corelease: Mechanism and Physiological Role

“Conversely, they slow or pause firing in response to rewards worse than predicted (98).”

“One possibility is that the glutamate released by dopamine terminals contributes to the prediction-error signal encoded in the firing rates of dopamine neurons (96, 97).”

“However, rather than using H + flux to produce ATP, the vacuolar H + pump uses ATP hydrolysis to drive H + transport into membranes of the secretory pathway, including endosomes, lysosomes, synaptic vesicles, and LDCVs (16). μ H+ in turn comprises both a chemical gradient (pH) and a membrane potential (ψ), and the tra…”

“The distribution of VGLUT1 and -2 originally suggested a correlation of VGLUT1 with synapses having a low probability of release (such as hippocampal synapses and parallel fiber synapses in the cerebellum) and VGLUT2 with synapses having a high probability of release (114).”

“One possibility is that the glutamate released by dopamine terminals contributes to the prediction-error signal encoded in the firing rates of dopamine neurons (96, 97).”

“Consistent with these changes in firing, extracellular dopamine measured by fast-scan cyclic voltammetry changes as predicted in rodents performing goal-directed tasks (99).”

“Considerable previous work has shown that only a fraction of the synaptic vesicles in a presynaptic bouton are available for evoked release, even after prolonged stimulation (113).”

“We do not know the stoichiometry of ionic coupling by the VGLUTs, but the sensitivity to pH (27, 43, 48) supports a H+ exchange mechanism despite the primary dependence of VGLUTs on ψ.”

“We do not know the stoichiometry of ionic coupling by the VGLUTs, but the sensitivity to pH (27, 43, 48) supports a H+ exchange mechanism despite the primary dependence of VGLUTs on ψ.”

“In addition to dopamine neurons that corelease glutamate (Hnasko and Edwards, 2012), we find that the midbrain contains a distinct set of glutamatergic projection neurons that do not coexpress dopaminergic markers (Kawano et al., 2006; Yamaguchi et al., 2007, 2011).”

“Co-release has a parallel with other neurotransmitters (49): Co-release implies that proton exocytosis need not have a unique regulatory mechanism; acidification would be initiated by the same Ca-dependent exocytotic release mechanisms that regulate glutamate release.”

“This difficulty arises, in part, because in addition to activating postsynaptic receptors, co-released neurotransmitters can modulate pre- and postsynaptic responses and even modulate the packaging of other neurotransmitters into synaptic vesicles [4].”

“Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors.”

“…glutamate transporter 2 (VGLUT2) (Kawano et al., 2006) and the ability of some dopamine neurons to co-release glutamate (Chuhma et al., 2014; Hnasko et al., 2010; Hnasko and Edwards, 2012; Stuber et al., 2010; Tecuapetla et al., 2010) have led to a surge of interest in VTA glutamate neurons.”

“, 1998), but often of functionally antagonist pairings, for example, GABA-glutamate, or GABA-acetylcholine or GABA-dopamine (Hnasko and Edwards, 2012; Vaaga et al., 2014).”

“nature, significant populations of GABAergic and glutamatergic projection neurons have been observed as well (Nair-Roberts et al., 2008; Stuber et al., 2010; Hnasko and Edwards, 2012).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript mechanism may be general (Amilhon et al., 2010; El Mestikawy et al., 2011; Gras et al., 2008; Hnasko and Edwards, 2012).”

“…a long time the dogma that one neuron stores and releases only one type of classical neurotransmitter has prevailed, accumulating evidence indicate that a vast number of exceptions exist (for recent reviews see (El Mestikawy et al., 2011; Hnasko and Edwards, 2012; Munster-Wandowski et al., 2016).”

“…of GSH tends to make it neuroactive, because all of its three individual amino acid residues can either function as neurotransmitters or interfere with glutamatergic neurotransmission, with Glu and Gly being excitatory and inhibitory neurotransmitters, respectively (Hnasko and Edwards, 2012).”

“Proton-dependent carriers, named vesicular glutamate transporters (VGLUTs) 1–3, are responsible for the vesicular accumulation of glutamate (for review see El Mestikawy et al., 2011; Hnasko and Edwards, 2012).”

“Co-release from cholinergic interneurons Although it goes against the Dale’s principle of one neurotransmitter per neuron, the concept of corelease is now more accepted (Hnasko & Edwards, 2012).”

“Further complexity is added by the fact that some VTA neurons co-release multiple neurotransmitters (Hnasko and Edwards, 2012; Trudeau et al., 2014).”

“Other changes—including homeostatic plasticity (Turri-giano et al. 1998; Borodinsky et al. 2004; Thiagarajan et al. 2005; Hnasko and Edwards 2012), changes in synaptic function due to retrograde cannabinoid signaling (Kreitzer and Regehr 2001; Wilson and Nicoll 2001), nitric oxide signaling…”

“Over the years much progress has been made in understanding the functional consequences of co-transmission in the nervous systems of vertebrates (see Svensson et al., 2001; Hnasko and Edwards, 2012; Vaaga et al., 2014).”

“Finally, neuromodulatory neurons often release multiple transmitters; we refer to previous reviews on the topic of co-transmission [26, 27].”

“This phenomenon has important ramifications for both the possible co-release of neurotransmitters as well as the regulation of the electrochemical gradients that drive transport activity (Guzman et al., 2011; Hnasko and Edwards, 2011).”

“Transmitter coexpression, cotransmission, and corelease have been reviewed recently and are not discussed here (Hnasko & Edwards 2012, Vaaga et al. 2014, Tritsch et al. 2016).”

“Interestingly, since glutamate itself is anionic, it acidifies the vesicles and activates the V-ATPases, enhancing the vesicular filling of glutamate via VGLUT [117].”

“This is perhaps not surprising since most, if not all neurons, appear to release one or more classical transmitters and one or more neuropeptides (Hnasko and Edwards, 2012; Vaaga et al., 2014) and this has been reported for the vast majority of neuropeptide systems (see Table 1 for several key…”

“Surprisingly, neurons sometimes even contain cotransmitters with supposedly opposing effects, such as excitatory glutamate and inhibitory g-aminobutyric acid (GABA).”

“A number of recent studies have demonstrated co-expression of VMAT2 or VAChT with VGLUTs (El Mestikawy et al., 2011; Hnasko and Edwards, 2011).”

“(E and F) Rotations were reversed to contraversive by apomorphine [E; 2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,56) = 4.”

“…activate genetically-defined cell types has led to a growing appreciation that mammalian neurons can release multiple fast-acting neurotransmitters (Hnasko and Edwards, 2012; Vaaga et al., 2014), subverting the classic notion that neuron classes can be defined by their ability to package and du…”

“…has been intensively studied in recent years, with the notion that glutamate corelease with another neurotransmitter encodes distinct information depending on activation levels (Hnasko and Edwards, 2012), and can convey temporalspecific information (Lapish et al., 2006, Lapish et al., 2007).”

“Identification of the vesicular glutamate transporters (VGLUTs) has greatly enhanced our ability to identify glutamatergic neurons, including many unexpected populations (El Mestikawy et al., 2011; Hnasko and Edwards, 2012).”

“…the brain (Trudeau, 2004; Gillespie et al., 2005; Zhou et al., 2005; Gras et al., 2008; Noh et al., 2010; Higley et al., 2011; Tritsch et al., 2012; Hnasko and Edwards, 2012; Münster-Wandowski et al., 2013; Nelson et al., 2014; Root et al., 2014a; Shabel et al., 2014; Qi et al., 2014; Zhang et…”

“…connections are weaker than those found in NAc SPNs. Weaker connections might identify release sites where glutamate cotransport potentiates dopamine release through vesicular synergy by increasing the packing of dopamine into vesicles (El Mestikawy et al., 2011; Hnasko and Edwards, 2012).”

“dynamically modulates both vesicular DpH and quantal size (Hnasko and Edwards, 2012).”

“It has since been demonstrated that more than one neurotransmitter can be released from a single neuron [65, 66].”

“, 2005), may contribute to glutamate cotransmission (Trudeau and Gutierrez, 2007; Hnasko and Edwards, 2012) and facilitate the vesicular storage of cotransmitters (Gras et al.”

“It is known that synaptic vesicles are acidic, and it is postulated that acidification of the synaptic cleft during neurotransmission might activate ASICs (Palmer et al., 2003; Hnasko and Edwards, 2012).”

“The functional dual transmitter phenotype Although dual transmitter neurons containing dopamine and either glutamate or GABA occur in multiple brain regions (Hnasko and Edwards, 2012), the spatiotemporal characteristics of their (co)release is only beginning to be explored (Chuhma et al.”

“VGLUT2-mediated glutamate uptake dissipates the vesicular electrical gradient enabling further activity of the vesicular proton pump, vesicular acidification and DA packing (47, 63, 98).”

“Corelease of multiple neurotransmitters from the same vesicle Release of multiple neurotransmitters from the same neuron or synapse is well documented (El Mestikawy et al., 2011; Granger et al., 2017; Hnasko and Edwards, 2012).”

“…glutamate, serotonin and glutamate, and acetylcholine and glutamate, recent evidence has suggested costorage in the same vesicles, but it remains unclear whether this is always the case (Gras et al., 2008; Hnasko et al., 2010; Hnasko and Edwards, 2012; Tritsch et al., 2012; Nelson et al., 2014).”

“In the CNS, there is convincing evidence for colocalization of dopamine (DA) with other low-molecular-mass transmitters that act on ionotropic postsynaptic receptors and therefore convey faster excitatory signals to the postsynaptic cell (Seal and Edwards, 2006; Hnasko and Edwards, 2012).”

“In recent years, however, it has become clear that the output of neurons can be more diverse (Hnasko and Edwards, 2012; Vaaga et al., 2014).”

“Because GABAR blockers are effective at transgenic excitatory synapses, we conclude that ambient GABA is available in these contacts, either by co-release with Glu or by spillover from neighbored GABAergic terminals (52, 53).”

“…been suggested to modulate vesicular transport: (1) influencing the membrane potential ( (cid:2) ψ ) by cation and anion fluxes and (2) a direct interaction between the heterotrimeric G-protein, G α o2 and VNTs (Omote et al., 2011; Blakely and Edwards, 2012; Hnasko and Edwards, 2012) ( Figure 2 ).”

“The biology of vesicular neurotransmitter transporters and their role in synaptic transmission have been covered in several recent reviews (Edwards, 2007; El Mestikawy, Wallen-Mackenzie, Fortin, Descarries, & Trudeau, 2011; Hnasko & Edwards, 2012).”

“…anatomical and functional characteristics of driving and modulating projections, independent of the source of the projection, that also match the physiological properties of VGLUT1 and VGLUT2 within a synapse (Blakely and Edwards, 2012; Fremeau et al, 2004; Hnasko and Edwards, 2012 for review).”

“In addition, one vesicular neurotransmitter transporter can increase the packaging of the other neurotransmitter into the same synaptic vesicle (SV), a process called vesicular synergy [4, 12, 13].”

“Other neurotransmitters, such as dopamine, can be expressed in Vgat/Vglut2-negative cells, and may contribute important modulatory functions (Hnasko and Edwards, 2012).”

“[3 7]”

“Both VGLUT1 and VGLUT2 proteins have been identi fi ed as glutamate transporters in the membrane of pre-synaptic vesicles and are therefore considered as molecular markers de fi ning the glutamatergic phenotype of neurons 82 – 84 .”

“TheDmH + reflects both electrical potential (Dc) and chemical pH gradients (DpH); transporters for different neurotransmitters depend to differing extents on Dc and DpH due to the charge on the substrate and the stoichiometry of coupling to H (Hnasko and Edwards, 2012).”

“The V-ATPase hub contained the majority of the V-ATPase subunits required for both SV and endosome acidification (23).”

“However, it is unknown whether all DA neurons contribute to GABA signaling or whether it is restricted to subpopulations like glutamate co-transmission from DA neurons (Hnasko and Edwards, 2012; Zhang et al., 2015; Silm et al., 2019).”

“Glutamate uptake depends mainly on Dw , whereas the activity of the vesicular GABA transporter VGAT depends on both parameters (Hnasko & Edwards, 2012).”

“Further increasing the complexity, 32 these neurotransmitters may be packaged within the same or different SV pools or released from distinct 33 axon terminals (Hnasko and Edwards, 2012; Saunders et al., 2015).”

“accordingly, glutamate receptors have been studied in great detail with regard to their key roles in synaptic transmission, synapse formation, axon guidance, and development of neuronal circuits [6,7].”

“The key components that execute SV acidification and neurotransmitter filling are the proton-pumping vacuolar H-ATPases (vATPases) and the vesicular neurotransmitter transporters.(7,8) These two groups of proteins initiate distinct processes: the vATPases form a proton electrochemical gradient (ΔμH+) across the membra…”

“As an alternative, optogenetic stimulation of the subset of neurons that produce a given neuro-modulator or neuropeptide can be used to drive neurochemical release ( 110 ), but this approach is confounded by the fact that most neurons co-release multiple neuromodulators and neuropeptides ( 111 ).”