Cholinergic synaptic circuitry in the macaque prefrontal cortex

Abstract

Surprisingly little is known about the synaptic architecture of the cholinergic innervation in the primate cerebral cortex in spite of its acknowledged relevance to cognitive processing and Alzheimer's disease. To address this knowledge gap, we examined serially sectioned cholinergic axons in supra- and infragranular layers of the macaque prefrontal cortex by using an antibody against the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT). The tissue bound antibody was visualized with both immunoperoxidase and silver-enhanced diaminobenzidine sulfide (SEDS) techniques. Both methods revealed that cholinergic axons make synapses in all cortical layers and that these synapses are exclusively symmetric. Cholinergic axons formed synapses primarily on dendritic shafts (70.5%), dendritic spines (25%), and, to a lesser extent, cell bodies (4.5%). Both pyramidal neurons and cells exhibiting the morphological features of GABAergic cells were targets of the cholinergic innervation. Some spiny dendritic shafts received multiple, closely spaced synapses, suggesting that a subset of pyramidal neurons may be subject to a particularly strong cholinergic influence. Analysis of synaptic incidence of cholinergic profiles in the supragranular layers of the prefrontal cortex by the SEDS technique revealed that definitive synaptic junctions were formed by 44% of the cholinergic boutons. An unexpected finding was that cholinergic boutons were frequently apposed to spines and small dendrites without making any visible synaptic specializations. These same spines and dendrites often received asymmetric synapses, presumably of thalamocortical or corticocortical origin. Present ultrastructural findings suggest that acetylcholine may have a dual modulatory effect in the neocortex: one through classical synaptic junctions on dendritic shafts and spines, and the other through nonsynaptic appositions in close vicinity to asymmetric synapses. Further physiological studies are necessary to test the hypothesis of the nonsynaptic release of acetylcholine in the cortex.

Simultaneous Release of Glutamate and Acetylcholine from Single Magnocellular “Cholinergic” Basal Forebrain Neurons

“…However, the ability to generate fast EPSCs through corelease of glutamate would allow for additional, rapid, and more punctate effects, more closely geared to the discharge patterns of the BF neurons. Furthermore, because much of the cholinergic innervation is onto dendritic shafts as opposed to pyramidal cell bodies (Beaulieu and Somogyi, 1991;Umbriaco et al, 1994;Mrzljak et al, 1995), it is likely that ACh also modulates the active conductance properties of these dendrites to facilitate or attenuate throughput and summation of synaptic inputs from other sources. If some of these afferents also release glutamate, then this could provide an additional excitatory input with much faster onset and offset rates than that mediated by mAChRs.…”

Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory

“…Anatomically, the synaptic circuitry of cholinergic prefrontal fibers includes symmetric synapses on pyramidal cells (27); symmetric synaptic morphology is characteristic of inhibitory mechanisms (28)(29)(30). It is unclear, however, why a direct inhibition of right prefrontal activity would be correlated with improved WM performance.…”

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

“…Furthermore, trihexyphenidyl and biperiden (Bolden et al 1992), mAChR antagonists which reduce typical APD-induced extrapyramidal symptoms (EPS), have been reported to cause complex clinical effects in patients with schizophrenia, e.g., working memory impairment (King 1990) and worsening of psychosis while decreasing negative symptoms (Tandon et al 1992). It is possible that clozapine and olanzapine influence clinical symptoms in schizophrenia via a direct effect upon main cholinergic transmission (Zorn et al 1994; Bymaster et al 1996).As has been demonstrated in rodents (Everitt and Robbins 1997) and primates (Mrzljak et al 1995), the nucleus basalis magnocellularis (NBM) or the basal forebrain consisting of the substantia innominata, the nucleus of Meynert, and the horizontal limb of the diagonal band, project cholinergic neurons to the cortex, whereas cholinergic interneurons exist mostly in the striatum (STR) and nucleus accumbens (NAC) (Kawaguchi et al 1995). These three regions are involved in various actions of APDs (Ichikawa and Meltzer 1999): 1) the medial prefrontal cortex (mPFC) has been suggested to be involved in the neural circuitry important for negative symptoms and cognition, e.g., working memory (Goldman-Rakic and Selemon 1997); 2) the STR is centrally involved in motor function; and 3) the NAC plays a key role in both psychosis and reward (Davis et al 1991; Kalivas and Nakamura 1999).…”

“…As has been demonstrated in rodents (Everitt and Robbins 1997) and primates (Mrzljak et al 1995), the nucleus basalis magnocellularis (NBM) or the basal forebrain consisting of the substantia innominata, the nucleus of Meynert, and the horizontal limb of the diagonal band, project cholinergic neurons to the cortex, whereas cholinergic interneurons exist mostly in the striatum (STR) and nucleus accumbens (NAC) (Kawaguchi et al 1995). These three regions are involved in various actions of APDs (Ichikawa and Meltzer 1999): 1) the medial prefrontal cortex (mPFC) has been suggested to be involved in the neural circuitry important for negative symptoms and cognition, e.g., working memory (Goldman-Rakic and Selemon 1997); 2) the STR is centrally involved in motor function; and 3) the NAC plays a key role in both psychosis and reward (Davis et al 1991;Kalivas and Nakamura 1999).…”