Cholinergic contributions to the cognitive symptoms of schizophrenia and the viability of cholinergic treatments

Abstract

Effective treatment of the cognitive symptoms of schizophrenia has remained an elusive goal. Despite the intense focus on treatments acting at or via cholinergic mechanisms, little remains known about the dynamic cholinergic abnormalities that contribute to the manifestation of the cognitive symptoms in patients. Evidence from basic neuroscientific and psychopharmacological investigations assists in proposing detailed cholinergic mechanisms and treatment targets for enhancement of attentional performance. Dynamic, cognitive performance-dependent abnormalities in cholinergic activity have been observed in animal models of the disorder and serve to further refine such proposals. Finally, the potential usefulness of individual groups of cholinergic drugs and important issues concerning the interactions between pro-cholinergic and antipsychotic treatments are addressed. The limited evidence available from patient studies and animal models indicates pressing research needs in order to guide the development of cholinergic treatments of the cognitive symptoms of schizophrenia.

Fig. 1

Schematic illustration of the main elements of prefrontal (PFC) circuitry mediating the detection of cues and of the tonic (dark red cholinergic neuron) and phasic (bright red cholinergic neurons) components of cholinergic neurotransmission (a). In the cortex, cholinergic transients are generated in part by the stimulation of ionotropic glutamate receptors and by glutamate released from mediodorsal thalamic (MD) afferents (Parikh et al., 2008, 2010). Mediodorsal inputs and thus glutamatergic transients are modulated by tonic (changes occurring on the scale of minutes) cholinergic stimulation of α4β2* nicotinic acetylcholine receptors (nAChRs). This allows levels of motivation and the subjects's readiness for utilizing external cues to influence the probability and efficacy of cue detection. An example of such tonic cholinergic activity measured by using microdialysis is shown in b, illustrating tonic prefrontal ACh before, during, and after four blocks of 8-min trials of sustained attention performance (data adopted from Paolone et al., 2010). In the PFC, glutamatergic and cholinergic transients interact to recruit efferent circuitry for the generation of the behavioral response. Figure c shows prefrontal glutamatergic and cholinergic transients recorded during cued trials yielding hits (the onset of the cue and the times of lever extension and correct lever presses are indicated below the abscissa). Note that the timing of detection-indicating behavior is related to the timing of the initial rise in transient cholinergic activity, as opposed to transient peak time (Howe and Sarter, 2010; Parikh et al., 2007).

Fig. 2

Illustration of hypotheses about attentional performance-associated abnormalities in the regulation of tonic cholinergic activity in controls and schizophrenia. Although reflecting the evidence described in Kozak et al. (2007), the data shown represent a paradigmatic scenario. In the absence of a challenge on top-down control (a), performance-associated increases in cholinergic activity remain relatively stable during the performance period in control subjects as well as the disease model. However, while unchallenged performance does not differ significantly between the animal model and healthy controls, robustly higher levels of cholinergic activity mediate the performance in the animal model. This finding has been discussed in terms of reflecting inordinate requirements on cognitive control in order to support performance even in the absence of challenges, in part because levels of cholinergic activity in the animal model and the absence of challenges were found to correspond with the elevated levels observed after a top-down challenges in healthy subjects (b). In control subjects, manipulations that evoke top-down control of attentional performance, including the presentation of a distractor, moderately impair attentional performance, followed by (partial) performance recovery toward the end of the session. In these subjects, cortical cholinergic activity levels during the distractor period exceed the levels seen during standard task performance. In contrast, the more severe disruption of performance in the animal model is associated with, and perhaps caused by (for evidence supporting a causal relationship see Kozak et al., 2007), a rapid loss and return to pre-task levels of task-associated cholinergic activity.

Fig. 3

Attentional performance-associated abnormalities in the regulation of transient cholinergic activity in controls and schizophrenia. Cholinergic transients are shown during hit (a) and miss trials (c) and during intertrial intervals (b), in control subjects and, speculatively, in schizophrenia. The hit-related cholinergic transient as well as the absence of such transients is based on evidence from intact animals (Howe and Sarter, 2010; Parikh et al., 2007). As discussed in the main text, cues that are detected by patients, albeit likely with lower probability and longer response latencies than in healthy controls. Such performance may be mediated via transients that rise later and exhibit slower and less linear rise rates, peak at lower levels and more variable time points, and decay less rapidly than in healthy control subjects (a). Indeed, slower decay rates, indicative of ongoing and slowly diminishing release, were demonstrated to be associated with less effective attentional performance (Howe et al., 2010). The attentional performance of animal models and patients is characterized in part by an increased rate of false alarms, specifically in response to performance challenges. As cholinergic transients are required for detection, we can speculate that such transients, although relatively poorly organized, occur sporadically during blank trials (c). Finally, in the absence of performance, transient cholinergic activity is speculated to fluctuate more markedly (b), indicative of a less effective and stable state of the prefrontal detection network. These speculations serve to illustrate that normalization of cholinergic neurotransmission are less a subject of simple corrections of levels of neurotransmitter activity but presumably require restoring the timing and rise and decay dynamics of such transients.