Cognitive Impairment and Dentate Gyrus Synaptic Dysfunction in Experimental Parkinsonism

Bonito‐Oliva, Alessandra; Pignatelli, Marco; Spigolon, Giada; Yoshitake, Takashi; Seiler, Stefanie; Longo, Francesco; Piccinin, Sonia; Kehr, Ján; Mercuri, Nicola Biagio; Nisticò, Robert; Fisone, Gilberto

doi:10.1016/j.biopsych.2013.02.015

Cited by 62 publications

(77 citation statements)

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“…Comparing our data with the data of Ferro et al (2005) and Braun et al (2012) (Table 2) pretreatment with desipramine in our study in contrast to the latter may explain the discrepancy, as a recent study in bilateral 6-OHDA-lesioned mice demonstrated a decreased noradrenaline level in the striatum and the hippocampus without giving desipramine before 6-OHDA injection, but no difference compared to control when desipramine was applied before the lesion (Bonito-Oliva et al, 2013). Other neurotransmitters such as noradrenaline may play an important role in regard to cognitive function in a mouse model of bilateral 6-OHDA lesion.…”

Section: A C C E P T E D Accepted Manuscriptcontrasting

confidence: 54%

“…A loss of dopaminergic fibers leads to a decrease in the number of neural progenitor cells (Baker et al, 2004;Freundlieb et al, 2006;Höglinger et al, 2004;O'Keeffe et al, 2009b;Suzuki et al, 2010). Furthermore, a decreased dopamine concentration in the hippocampus has been shown after dopamine depletion in the nigrostriatal system (Bonito-Oliva et al, 2013;Costa et al, 2012).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…The effect of dopaminergic therapy on cognitive dysfunction in PD remains unclear. One study showed an improvement of working memory with PPX treatment (Costa et al, 2009), whereas others could not find any effect on cognitive function (Bonito-Oliva et al, 2013;Brusa et al, 2003;Kim et al, 2009). With regard to L-DOPA, it has been reported that cognitive function can be improved (Bonito-M A N U S C R I P T…”

Section: Introductionmentioning

confidence: 99%

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Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

et al. 2015

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Section: A C C E P T E D Accepted Manuscriptcontrasting

confidence: 54%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

et al. 2015

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“…On the other hand, bilateral injections of 6-OHDA in the mouse striatum selectively impaired the performance in the longterm, but not in the short-term NOR test (Bonito-Oliva et al 2013). In this study, the authors attributed the memory impairment to a deficient long-term potentiation in the dentate gyrus, but not the CA1 area of the hippocampus.…”

Section: -Ohda-and Mptp-based Rodent Modelsmentioning

confidence: 64%

“…In a similar model, chronic administration of MK-801, a noncompetitive NMDA receptor antagonist, resulted in a mild improvement of the performance, accompanied by a partial recovery of dopaminergic transmission in SNpc and striatum (Hsieh et al 2010). The authors suggest that the MPTP injection induces an excitotoxic release of glutamate in the striatum and a consequent neuroinflammatory response in the hippocampus, which is rich in NMDA receptors and mediates memory functions (Hsieh et al 2010).On the other hand, bilateral injections of 6-OHDA in the mouse striatum selectively impaired the performance in the longterm, but not in the short-term NOR test (Bonito-Oliva et al 2013). In this study, the authors attributed the memory impairment to a deficient long-term potentiation in the dentate gyrus, but not the CA1 area of the hippocampus.…”

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Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

et al. 2013

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Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet clinical condition. At the preclinical level, the large majority of studies aiming at defining mechanisms and testing novel therapies have similarly focused on the motor aspects of PD. Unfortunately, deterioration of the executive functions, such as attention, recognition, working memory, and problem solving, often appear in an early, premotor phase of the disease and progressively increase in intensity, negatively affecting the quality of life of 50% -60% of PD patients. At present, the cellular mechanisms underlying cognitive impairments in PD patients are largely unknown and an adequate treatment is still missing. The preclinical research has recently developed new animal models that may open new perspectives for a more integrated approach to the treatment of both motor and cognitive symptoms of the disease. This review will provide an overview on the cognitive symptoms occurring in early PD patients and then focus on the rodent and nonhuman primate models so far available for the study of discriminative and spatial memory attention and learning abilities related to this pathological condition. Cognitive deficits in Parkinson's diseaseParkinson's disease (PD) is a chronic neurodegenerative disorder affecting over four million people worldwide (Dorsey et al. 2007). It is classically characterized by the emergence of motor symptoms such as rigidity, tremor, postural unbalance, and bradykinesia/akinesia (Braak et al. 2003;Jankovic 2008). However, PD also involves nonmotor symptoms (NMS) (Chaudhuri et al. 2006;Jankovic 2008) that appear in the early, often premotor, phase of the disease (Abbott et al. 2005;Abbott 2007;Claassen et al. 2010) and significantly contribute to the impairment of the quality of life of 50%-60% of PD patients (Aarsland et al. 2012). Among others, NMS include olfactory dysfunction, REM sleep disorder, neuropsychiatric disturbances, and cognitive deficits (Schrag et al. 2004;Chaudhuri and Odin 2010). All these symptoms develop independently from each other in the early phase of the disease, and progressively increase in intensity, often leading to dementia in the late phase (Cools et al. 2001;Goetz et al. 2008).Neuropsychiatric mood-related disorders are rather common in PD (Cummings 1992;Schrag et al. 2004) with a prevalence of 20% (Reijnders et al. 2008), and manifest as apathy, depression, and anxiety.On the other hand, cognitive impairments associated with PD are mainly related to the executive functions, resulting in a phenotype resembling that of frontal lobe patients (Robbins and Arnsten 2009), with deficits in attention (Ballard et al. 2002), planning, concept formation, and working memory (Kehagia et al. 2010). In particular, memory deterioration aff...

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Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

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Piccinin

et al. 2016

Synapse

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Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease. Synapse 70:223-230,

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Cognitive Impairment and Dentate Gyrus Synaptic Dysfunction in Experimental Parkinsonism

Cited by 62 publications

References 47 publications

Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

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