Paying attention with a compromised cholinergic system: attenuated activation of cholinergic neurotransmission in attentional task-performing CHT+/- mice

Prefrontal cholinergic neurotransmission is necessary for sustained attentional performance. In rats, prefrontal acetylcholine (ACh) release reaches 140% over baseline during the performance of a sustained attention task (SAT; St. Peters et al., 2011a). SAT performance also increases the density of choline transporters (CHT) in synaptic plasma membranes (Apparsundaram et al., 2005), which we hypothesize is needed to sustain elevations of cholinergic activity and behavioral responses. Here we employed the SAT recently adapted for use in mice (St. Peters et al., 2011b) and developed new techniques that permit monitoring of ACh release via microdialysis of mice performing the SAT in order to determine the impact of genetically manipulated levels of choline transporter capacity. First, reverse dialysis of atropine (50 µM) increased ACh release levels in naive WT mice. In contrast, CHT+/- mice could not sustain these increases, consistent with changes observed in levels of muscarinic receptors in the CHT +/- mice (Bazalakova et al., 2007). However, SAT performance did not differ significantly between WT controls and CHT+/- mice. Furthermore, basal (absolute) levels of ACh release were comparable between strains. However, performance-associated increases in ACh release were strikingly attenuated in CHT+/- mice, reaching 40% over basal levels versus 130% in WT. Performance-associated increases in ACh release in CHT+/- mice were TTX-sensitive, similar to release monitored in WT mice (1 µM via reversed dialysis). To determine whether cholinergic activity was necessary for SAT performance in CHT+/- mice we then removed basal forebrain cholinergic neurons by infusing murine-p75NTR-saporin obtaining similar impairment on SAT performance in both strains. Finally, and because cholinergic activity modulates cortical circuitry primarily via nAChR, mecamylamine (MEC; 50 µM) was reverse dialyzed during SAT performance. WT mice were only moderately impaired in the SAT task, whereas the performance of CHT+/- mice rapidly declined and the performance-associated ACh levels rapidly returned to the pre-task levels. In summary CHT+/- mice are able to perform the basic SAT, despite attenuated levels of cholinergic neurotransmission, likely as a result of compensatory postsynaptic mechanisms. However, their attentional performance and underlying cholinergic signaling exhibit heightened sensitivity to behavioral and pharmacological challenges. Together, these findings suggest that CHT+/- mice are an important model for the impaired cognitive control of attentional performance that is a common symptom of ADHD, schizophrenia and other cognitive disorders.