Parkinson’s disease (PD) is a characterized, in addition to loss of dopaminergic neurons in the substantia nigra, by loss of cholinergic neurons in the basal nucleus (Zarow et al., 2003) and pathology of alpha-synuclein, a protein implicated in familial PD, in this region concurrently with pathology of alpha-synuclein pathology in the substantia nigra (Braak et al., 2003), as well as decrease in the activity of choline acetyltransferase, the rate limiting enzyme in the synthesis of acetylcholine (Ziabreva et al., 2006). Mild cognitive deficits are also observed in the early stages of PD (Elgh et al., 2009; Mamikonyan et al., 2009). Mice over-expressing the human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn) present progressive sensorimotor and non-motor behavioral abnormalities reminiscent of the pre-manifest early stages of PD (Magen and Chesselet, ’10) and subsequently exhibit a loss of striatal DA (Lam et al. ’11). We now examined whether these mice also exhibit cognitive deficits in tests sensitive to cholinergic function, and whether they present cholinergic deficits.
Thy1-aSyn mice on a mixed C57BL/6-DBA/2 background presented spatial working memory deficits in the Y-maze which showed progression from 3-4 to 5-6 months and to 7-9 months. Thy1-aSyn mice also showed spatial memory deficits in the novel place recognition test and recognition memory deficits in the novel object recognition test at 4-5 months of age. In a reversal learning task at 4-5 months, Thy1-aSyn mice learned the initial contingency rule as equally well as WT littermates, but were impaired in learning a reversal of this rule, mirroring the cognitive inflexibility displayed by early PD patients in similar tasks. Expression of both proteinase-K resistant and non-resistant alpha-synuclein in the medial septum and the basal nucleus, two major regions of cholinergic input into the forebrain, was increased in Thy1-aSyn mice at 5 months of age, and cholinergic neurons in both regions expressed both human and mouse alpha-synuclein in Thy1-aSyn mice, while endogenous (murine) alpha-synuclein expression was either lower or absent in cholinergic neurons in WT mice. However, morphological features of the cholinergic neurons such as cell body diameter did not change in either the basal nucleus or the septum. Acetylcholine levels decreased by 30% in the cortex of Thy1-aSyn mice at 6 months, further suggesting a link between acetylcholine pathology and the cognitive deficits.
Our data indicate that Thy1-aSyn mice display cognitive dysfunction at an early age, which is associated with decreased acetylcholine levels. As the cognitive tests used are sensitive to cholinergic function (Barker et al., 2008; Yang et al., 2009; Botton et al., 2010), future pharmacological studies will attempt to reverse these deficits using cholinergic agonists and/or acetylcholinesterase inhibitors. A study with an acute nicotine treatment is to be performed soon, to determine whether nicotine can reverse the cognitive deficits, which might point to a causal relation between the cognitive deficits and the compromised cholinergic system. In addition, the cognitive phenotype faithfully reproduces the early cognitive deficits in PD, whereas the lack of any neuropathology in cholinergic neurons suggests that the Thy1-aSyn models mild cognitive deficits rather than dementia, which is mostly associated with a gross neuropathology. Thus, it can serve as a basis for the testing of cognitive enhancers other than cholinergic agents.
