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It has been recognized for decades that neurons
It has been recognized for decades that neurons in the mammalian central nervous system may release both a fast-acting, typically amino acid derived neurotransmitter such as glutamate or GABA, and a second peptidergic neuromodulatory molecule such as neuropeptide Y, substance P, or cholecystokinin. Typically, the fast-acting neurotransmitter is released in response to a single action potential and its effect via activation of ionotropic receptors on the membrane potential of a postsynaptic neuron is easily detected. In contrast, although peptide expression often demarcates distinct classes of intermingled neurons, such as somatostatin (SST) vs. vasoactive intestinal polypeptide (VIP) expressing cortical interneurons (Rudy et al., 2011) or dynorphin vs. enkephalin expressing striatal projection neurons (Steiner and Gerfen, 1998), the patterns of activity that trigger peptide release and the physiological effects of peptide-transmission remain unclear. Thus for most neurons, the relationship between pre and postsynaptic activity is only understood for a single primary neurotransmitter. The ability to optogenetically 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 release a single primary neurotransmitter. Examples include spinal interneurons that release GABA and glycine (Jonas et al., 1998), midbrain dopaminergic neurons that also release glutamate and/or GABA (Stuber et al., 2010, Tecuapetla et al., 2010, Tritsch et al., 2012, Tritsch et al., 2014), and habenula-projecting neurons that release both GABA and glutamate (Root et al., 2014, Shabel et al., 2014). In the central nervous system, Sulfasalazine receptor (ACh) and the activity of cholinergic neurons has been shown to facilitate learning and memory formation, increase alertness and attention, and signal behaviorally relevant sensory cues (Sarter et al., 2009, Hasselmo and Sarter, 2011, Picciotto et al., 2012). These behavioral functions are mediated by multiple populations of neurons that produce and release ACh. However, the specialized functions of each ACh-releasing population are largely unknown. In the cerebral cortex, ACh is released from long-range axons projecting from basal forebrain neurons (Jones, 2004), with a potential contribution from local cholinergic interneurons (Von Engelhardt et al., 2007, Consonni et al., 2009, Cauli et al., 2014). Like the cortex, the striatum has both local cholinergic interneurons and long-distance innervation from the brainstem cholinergic centers (Calabresi et al., 2000). The hippocampus and neighboring entorhinal cortex, however, are innervated by extrinsic cholinergic inputs from the medial septum and horizontal and diagonal limbs of the band of Broca (MSDB; Teles-Grilo Ruivo and Mellor, 2013) and by intrinsic cholinergic interneurons (Frotscher et al., 1986, Frotscher et al., 2000, Romo-Parra et al., 2003, Yi et al., 2015). In these systems, ACh can activate ionotropic, excitatory nicotinic acetylcholine receptors (nAChRs) or metabotropic muscarinic acetylcholine choline receptors (mAChRs). These receptors then regulate postsynaptic cellular excitability and the synaptic release of other neurotransmitters from the presynaptic cell, which can alter synaptic plasticity (Picciotto et al., 2012, Arroyo et al., 2014). In the forebrain, the first identified co-transmitter to be released with ACh was glutamate. VGLUT3, a vesicular glutamate transporter, is expressed by subpopulations of cholinergic neurons, and, in the striatum, is necessary for glutamate release from striatal cholinergic interneurons (Higley et al., 2011). Interestingly, serotonergic neurons that innervate the striatum also express VGLUT3 (Gras et al., 2002) and release glutamate in the hippocampus (Varga et al., 2009). The functional consequences of VGLUT3-dependent glutamate release from these neurons is not fully understood and the protein may facilitate in vesicular loading of glutamate as well as of acetylcholine and monoamines (El Mestikawy et al., 2011). Little else is known about glutamate corelease from cholinergic neurons, and for the remainder of this mini review, we focus on the evidence for GABA and ACh cotransmission throughout the nervous system and speculate on potential functional consequences.