Neuromodulation by acetylcholine: examples from schizophrenia and depression
Introduction
Acetylcholine (ACh) is a potent regulator of neuronal activity throughout the peripheral and central nervous system [1, 2]; however, the specific contributions of cholinergic neuromodulation to circuit function in the healthy brain and in psychiatric illness have been difficult to dissect, due to its pleiotropic actions on neuronal excitability, synaptic transmission, and network dynamics. In the last few years, technological innovations in the areas of molecular genetics, physiology, and human imaging have provided new ways to understand how neuromodulation shapes circuits and behavior. In this review, we outline recent progress in understanding how cholinergic signaling contributes to circuits involved in two groups of psychiatric disorders, schizophrenia and major depressive disorder (MDD). Continued technical innovation will continue to bring us closer to the ideal of translating fundamental neuronal mechanisms to the understanding and treatment of psychiatric illness.
The two sources of ACh in the CNS are (1) projection nuclei that diffusely innervate distal areas and (2) local interneurons that are interspersed among their cellular targets. Cholinergic projection nuclei include the pedunculopontine (PPT) and laterodorsal (LDT) tegmental areas and the basal forebrain complex, including the medial septum [3, 4, 5]. In contrast, cholinergic interneurons are typified by the tonically active cells of the striatum and nucleus accumbens [6]. There is also evidence for a small population of cholinergic interneurons in the neocortex [7, 8] and hippocampus [9].
The actions of ACh are mediated by two major classes of receptors: metabotropic muscarinic receptors (mAChRs) and ionotropic nicotinic receptors (nAChRs) [reviewed in [10, 11]]. Briefly, mAChRs are G protein-coupled and categorized by signaling through either Gαq (M1, M3, M5 subtypes) or Gαi (M2, M4 subtypes). In contrast, nAChRs function as nonselective, excitatory cation channels and occur as either homomeric or heteromeric assemblies of a large family of alpha-subunits (α2–α7) and beta-subunits (β2–β4).
Considerable debate has focused on whether cholinergic signaling occurs via traditional synapses with closely apposed presynaptic and postsynaptic membranes or via volume transmission mediated by diffusion through the extracellular space [12, 13]. While a detailed discussion of this topic is beyond the present scope, several studies have suggested that ACh acts primarily by volume transmission. There is an anatomical mismatch between the sites of ACh release and the location of cholinergic receptors [14, 15, 16], and extracellular levels of ACh fluctuate in a manner that appears to be inconsistent with localized clearance of a synaptic transmitter [17, 18, 19]. More recently, however, it has become clear that volume transmission may be insufficient for the rapid transfer of cholinergic signals measured using electrochemical recordings in behavioral tasks such as prefrontal cortex (PFC)-dependent cue-detection or sustained attention [20••, 21]. In addition, optogenetic stimulation of endogenous Ach release has revealed fast excitatory transients mediated by nAChRs in neocortical GABAergic interneurons [22•, 23•, 24]. These rapid cholinergic signals are a key element in a cortical network underlying auditory fear learning [25••]. The development of tools allowing more precise stimulation of ACh neurons in vivo [22•, 23•, 24] has been an innovation that has already altered our view of cholinergic neuromodulation.
Section snippets
Cholinergic function and dysfunction in neuropsychiatric disease
The neuromodulatory effects of ACh signaling are critical for normal function of numerous brain systems. Accordingly, abnormalities in the cholinergic system are known to contribute to a number of psychiatric and neurological illnesses. In the periphery, autoantibodies to muscle nAChRs contribute to myasthenia gravis [26, 27]. Moreover, loss of cholinergic neurons and receptors in the brain contribute to the cognitive decline in Alzheimer's disease [28] and may contribute to the progression of
Conclusions
Despite decades of work, a complete understanding of the role of ACh in brain function remains elusive. However, recent methodological advances for monitoring and manipulating cholinergic systems have broadened our knowledge of the cellular mechanisms underlying ACh signaling. Similarly, new human imaging studies have highlighted the role for distinct cholinergic systems in behavior. One principal conclusion to be drawn from the wealth of current data is that cholinergic modulation is best
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by a Smith Family Award, a Sloan Research Fellowship, and NIH grant MH099045 (MJH) and NIH grants DA014241, MH077681 and DA033945 (MRP).
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