Editors' ChoiceAlzheimer’s Disease

Acetylcholine: Working on Working Memory

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Science Translational Medicine  21 Dec 2011:
Vol. 3, Issue 114, pp. 114ec208
DOI: 10.1126/scitranslmed.3003583

Alzheimer’s dementia is associated with the loss of cholinergic neurons that produce acetylcholine, but drugs that increase acetylcholine levels at the synapse don’t always result in significantly improved cognition. Are the drugs not good enough, or do we need to shift our focus to other neurotransmitters? Croxson and colleagues have now identified more precisely the cognitive dysfunction resulting from loss of cholinergic neurons.

The investigators studied the effects of specifically killing cholinergic neurons in the well-differentiated prefrontal cortex of rhesus monkeys, providing an approximation of the effects of reduced acetylcholine in human Alzheimer’s disease and other forms of dementia. Croxson et al. used a targeted immunotoxin to deplete such neurons in the lateral and orbital prefrontal cortex. Of note, the monkeys with prefrontal cholinergic lesions showed no deficit in a model of human episodic memory. Similarly, these lesions did not impair strategy implementation, which is a task of executive function. However, cholinergic lesions in the prefrontal cortex resulted in impaired learning in a delayed response task, which models working memory (a system that is theorized to hold and manipulate information in the short term).

The study by Croxson and colleagues clarifies the role of prefrontal acetylcholine in cognitive function by pinpointing working memory—as opposed to episodic memory and executive function—as the most susceptible to reduced acetylcholine transmission. These findings have implications for the pharmacologic treatment of Alzheimer’s disease by suggesting that the increase of acetylcholine in the prefrontal cortex can only be expected to improve working memory rather than all of the diverse cognitive functions of that brain region. This finding highlights the need to identify other neurotransmitter systems that mediate cognitive dysfunction in Alzheimer’s disease so that a multimodal pharmacologic approach can be developed. Finally, the work of Croxson et al. explains why other forms of dementia with greater cholinergic neuron loss, such as Lewy body disease, are associated with working memory dysfunction.

P. L. Croxson et al., Cholinergic modulation of a specific memory function of prefrontal cortex. Nat. Neurosci. 14, 1510–1512 (2011). [Abstract]

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