Cognitive dysfunction and depression in Parkinson’s disease: what can be learned from rodent models?

Abstract

Parkinson’s disease (PD) has for decades been considered a pure motor disorder and its cardinal motor symptoms have been attributed to the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and to nigral Lewy body pathology. However, there has more recently been a shift in the conceptualization of the disease, and its pathological features have now been recognized as involving several other areas of the brain and indeed even outside the central nervous system. There are a corresponding variety of intrinsic non‐motor symptoms such as autonomic dysfunction, cognitive impairment, sleep disturbances and neuropsychiatric problems, which cannot be explained exclusively by nigral pathology. In this review, we will focus on cognitive impairment and affective symptoms in PD, and we will consider whether, and how, these deficits can best be modelled in rodent models of the disorder. As only a few of the non‐motor symptoms respond to standard DA replacement therapies, the quest for a broader therapeutic approach remains a major research effort, and success in this area in particular will be strongly dependent on appropriate rodent models. In addition, better understanding of the different models, as well as the advantages and disadvantages of the available behavioural tasks, will result in better tools for evaluating new treatment strategies for PD patients suffering from these neuropsychological symptoms.

Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice

“…Thus, since the critical phenotype of PD is motor impairment, interpretation of cognitive impairments from the motor readouts may not be accurate as the poor performance of the animal may be due to motor impairment rather than its cognitive capacity (Lindgren & Dunnett, 2012). Interestingly, all motor parameters analyzed during the cognitive tests were normal in the LRRK2-Tg mice, suggesting that the impairment in cognitive functions of LRRK2-Tg mice may not be due to motor impairments.…”

Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat

“…Consistent with a possible integrative role of the LHb‐RMTg pathway in regulating both DA and 5‐HT functions, the findings of a recent combined behavioral/manganese‐enhanced magnetic resonance imaging study indicate that the LHb couples the DA and 5‐HT systems (Sourani et al, ). A functional coupling of DA and 5‐HT systems via the LHb‐RMTg and other circuits discussed here may be relevant to explain the involvement of DA in psychomotor symptoms of depression (Sobin and Sackheim, 1997; Buyukdura et al, ), as well as the role of 5‐HT in nonmotor symptoms in Parkinson's disease such as depression and anxiety (Tan et al, ; Lindgren and Dunnett, ).…”

Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function

“…The pattern of reduced depressive-like behavior diverged dramatically at 12 months, as symptomatic A53T mice (WHT latency<20 s) adopted an immobile posture throughout the FST period, while asymptomatic A53T animals maintained lower immobility scores compared to WT. The increase in FST immobility scores in symptomatic A53T mice suggests that increased depressive-like behaviors observed in other rodent models of PD (primarily neurotoxin models) may be linked to the acute loss of dopaminergic tissues and development of motor impairment rather than the development of pre-motor symptoms analogous to the co-morbidity of depression with PD (for review see [66]). Successfully modeling the constellation of non-motor symptoms that accompany PD, especially those that typically occur prior to clinical diagnosis, remains a pressing goal for pre-clinical researchers that could provide a means for testing prophylactic treatments or other therapeutic measures [15], [16].…”