Impaired Cholinergic Excitation of Prefrontal Attention Circuitry in the TgCRND8 Model of Alzheimer's Disease

Abstract

Attention deficits in Alzheimer's disease can exacerbate its other cognitive symptoms, yet relevant disruptions of key prefrontal circuitry are not well understood. Here, in the TgCRND8 mouse model of this neurological disorder, we demonstrate and characterize a disruption of cholinergic excitation in the major corticothalamic layer of the prefrontal cortex, in which modulation by acetylcholine is essential for optimal attentional function. Using electrophysiology with concurrent multiphoton imaging, we show that layer 6 pyramidal cells are unable to sustain cholinergic excitation to the same extent as their nontransgenic littermate controls, as a result of the excessive activation of calcium-activated hyperpolarizing conductances. We report that cholinergic excitation can be improved in TgCRND8 cortex by pharmacological blockade of SK channels, suggesting a novel target for the treatment of cognitive dysfunction in Alzheimer's disease.

Significance statement: Alzheimer's disease is accompanied by attention deficits that exacerbate its other cognitive symptoms. In brain slices of a mouse model of this neurological disorder, we demonstrate, characterize, and rescue impaired cholinergic excitation of neurons essential for optimal attentional performance. In particular, we show that the excessive activation of a calcium-activated potassium conductance disrupts the acetylcholine excitation of prefrontal layer 6 pyramidal neurons and that its blockade normalizes responses. These findings point to a novel potential target for the treatment of cognitive dysfunction in Alzheimer's disease.

Keywords: Alzheimer's model; SK channels; acetylcholine receptors; afterhyperpolarization potential (AHP); corticothalamic; prefrontal cortex.