Spatial deficits in a mouse model of Parkinson disease

Leonibus, Elvira De; Pascucci, Tiziana; Lopez, S.; Oliverio, Alberto; Amalric, Marianne; Mele, Andrea

doi:10.1007/s00213-007-0862-4

Cited by 70 publications

(55 citation statements)

References 45 publications

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“…Our conclusions are consistent with observations from rodent models of PD, where lesioning of DA neurons in the SNc results in deficits of visuospatial function (24)(25)(26). However, these models make no distinction between loss of DA signaling versus loss of DA neurons and do not separate performance from cognitive deficits.…”

Section: Object Memory and Visuospatial Learning Are Partially Restorsupporting

confidence: 90%

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Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

Darvas

Palmiter

2009

Proc. Natl. Acad. Sci. U.S.A.

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The striatum is a vital substrate for performance, procedural memory, and learning. The ventral and medial striatum are thought to be critical for acquisition of tasks while the dorsolateral striatum is important for performance and habitual enactment of skills. Evidence based on cortical, thalamic, and amygdaloid inputs to the striatum suggests a medio-lateral zonation imposed on the classical dorso-ventral distinction. We therefore investigated the functional significance of dopaminergic signaling in cognitive tasks by studying dopamine-deficient (DD) mice and mice with dopamine signaling restored to only the dorsolateral (DL) striatum by viral rescue (vrDD-DL mice). Whereas DD mice failed in all of the tasks examined here, vrDD-DL mice displayed intact discriminatory learning, object recognition, visuospatial learning and spatial memory. Acquisition of operant behavior for food rewards was delayed in vrDD-DL mice and their motivation in a progressive ratio experiments was reduced. Therefore, dopaminergic signaling in the dorsolateral striatum is sufficient for mice to learn several different cognitive tasks although the rate of learning some of them was reduced. These results indicate that dopaminergic signaling in the ventromedial striatum is not absolutely necessary for mastery of these behaviors, but may facilitate them.knockout ͉ learning ͉ memory ͉ tyrosine hydroxylase ͉ viral gene transfer M idbrain dopamine (DA) neurons mediate not only motor control, but also play a crucial role in many emotional and cognitive functions (1). DA projections from the ventral tegmental area (VTA) to the ventral striatum play a key role in reward, motivation, formation of Pavlovian associations and Pavlovian to instrumental transfer (2-5). DA projections from the substantia nigra pars compacta (SNc) to the dorsomedial striatum contribute to goal-directed operant learning and projections to the dorsolateral striatum contribute to stimulusresponse learning (6-8). It is widely accepted that the ventral striatum is essential for the acquisition of learned behavior, whereas the dorsolateral striatum is thought to be important for general performance, rather than acquisition of learning (9-11). Within this theoretical framework, the transition from goaldirected actions during early learning to stimulus-response controlled habits reflects a reallocation from ventral to dorsal striatal control over behavior (12,13). Recently, a spiraling mechanism has been proposed through which a cascade of serial connectivity linking the ventral striatum with progressively more dorsal regions of the striatum allows the ventral striatum to exert control, mediated by DA neurotransmission, over dorsal striatal processes (14,15).Based on the associations of cognitive and psychiatric symptoms with Parkinson's disease (PD) (16-18), the striatum is also thought to contribute to memory and visuospatial learning (19)(20)(21). In accordance with these observations, data from rodent models of PD indicate that the dorsal striatum contributes to various for...

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Section: Object Memory and Visuospatial Learning Are Partially Restorsupporting

confidence: 90%

“…In accordance with these observations, data from rodent models of PD indicate that the dorsal striatum contributes to various forms of learning and memory (22)(23)(24)(25)(26).…”

supporting

confidence: 54%

Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

Darvas

Palmiter

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Consistently, extensive DA lesions, obtained through either medial forebrain bundle or dorsal striatum 6-hydroxydopamine (6-OHDA) administrations, have been found to impair memory in the spatial version of the Morris water maze in rats (Miyoshi et al, 2002;Mura and Feldon, 2003;Whishaw and Dunnett, 1985). Furthermore, it has been recently shown that partial bilateral DA depletion of the dorsal striatum impairs spatial discrimination in the object-place association task in mice, and that this effect is specific for spatial information (De Leonibus et al, 2007), thus providing an useful animal model of cognitive deficit in the early stages of PD.…”

Section: Introductionmentioning

confidence: 81%

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Leonibus

Managò

Giordani

et al. 2008

Neuropsychopharmacol

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Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudateputamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.

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“…For the future it might be interesting to study whether the Cx30 Ϫ/Ϫ /Cx47 Ϫ/Ϫ and Cx30 Ϫ/Ϫ /Cx47 ϩ/Ϫ mice are impaired in the one-trial inhibitory avoidance task. This test is known to be less sensitive to motor impairments and has been used to demonstrate preserved learning and memory functions in a mouse model of Parkinson disease (De Leonibus et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Panglial Gap Junctional Communication is Essential for Maintenance of Myelin in the CNS

et al. 2012

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In this study, we have investigated the contribution of oligodendrocytic connexin47 (Cx47) and astrocytic Cx30 to panglial gap junctional networks as well as myelin maintenance and function by deletion of both connexin coding DNAs in mice. Biocytin injections revealed complete disruption of oligodendrocyte-to-astrocyte coupling in the white matter of 10-to 15-d-old Cx30/Cx47 double-deficient mice, while oligodendrocyte-to-oligodendrocyte coupling was maintained. There were no quantitative differences regarding cellular networks in acute brain slices obtained from Cx30/Cx47 double-null mice and control littermates, probably caused by the upregulation of oligodendrocytic Cx32 in Cx30/Cx47 double-deficient mice. We observed early onset myelin pathology, and ϳ40% of Cx30/Cx47 doubledeficient animals died within 42 to 90 d after birth, accompanied by severe motor impairments. Histological and ultrastructural analyses revealed severe vacuolization and myelination defects in all white matter tracts of the CNS. Furthermore, Cx30/Cx47 double-deficient mice exhibited a decreased number of oligodendrocytes, severe astrogliosis, and microglial activation in white matter tracts. Although less affected concerning motor impairment, surviving double-knock-out (KO) mice showed behavioral alterations in the open field and in the rotarod task. Vacuole formation and thinner myelin sheaths were evident also with adult surviving double-KO mice. Since interastrocytic coupling due to Cx43 expression and interoligodendrocytic coupling because of Cx32 expression are still maintained, Cx30/Cx47 double-deficient mice demonstrate the functional role of both connexins for interastrocytic, interoligodendrocytic, and panglial coupling, and show that both connexins are required for maintenance of myelin.

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Spatial deficits in a mouse model of Parkinson disease

Abstract: These results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.

Cited by 70 publications

References 45 publications

Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Panglial Gap Junctional Communication is Essential for Maintenance of Myelin in the CNS

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