Modelos animais de disfunção colinérgica: papel da acetilcolina na cognição

Abstract

The release of the neurotransmitter acetylcholine (ACh) depends on the vesicular loading by the vesicular acetylcholine transporter (VAChT). ACh is important for different cognitive functions such as learning, memory and attention. We have generated mice with distinct expression levels of VAChT and consequently ACh release to probe for functional roles of synaptic vesicle filling in cholinergic activity and cognitive function. We provided evidence that the reduction of ACh release or injection of muscarinic receptor antagonist blocked object recognition long term memory (LTM) without affecting remote memory. Using a second mouse line in which we selectively eliminated VAChT in the basal forebrain with the cre-loxP method, we suggest that the cholinergic projections of the basal forebrain neurons are crucial for LTM. The introduction of a Tk-Neo resistance cassette added approximately 1.5 kb downstream from the VAChT stop codon caused a major reduction of VAChT expression in the brain, but relatively preserved peripheral function. We studied the consequence of the reduction of VAChT with two different strains of mice, and observed an increase of locomotor activity without changes in anxiety. We also demonstrated that genetic removal of the Neomycin resistance cassette rescues VAChT expression and the hyperactivity phenotype. Striatal activity plays important roles in controlling motor functions and rewardrelated behaviours and it is the major brain region affected in several motor diseases such as Parkinsons disease and Huntingtons disease. Dopamine-acetylcholine balance in the striatum is believed to be critical for proper motor function and behaviour. To understand the specific contribution of the cholinergic neurons in the striatum, we also developed a mouse line in which we selectively eliminated VAChT in the striatum. We found surprisingly that this mice do not show changes in motor performance and motor learning. However, decreased cholinergic function in the striatum seems to specifically improve the response of mice in the forced-swimming task, suggesting that striatal VAChT might be a novel target for treatment of depression associated with Parkinsons disease.