Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Morice, Elise; Billard, Jean‐Marie; Denis, Cécile V.; Mathieu, Flavie; Betancur, Catalina; Epelbaum, Jacques; Giros, Bruno; Nosten‐Bertrand, Marika

doi:10.1038/sj.npp.1301354

Cited by 102 publications

(77 citation statements)

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“…M Bellesi and F Conti of hippocampal LTD (Morice et al, 2007). On these bases, it has been suggested that LTD could have a key role in modulating cognitive flexibility as well as in other complex cognitive functions (Morice et al, 2007;Nicholls et al, 2008).…”

Section: Ly379268 Blocks Cef-induced Ppi Impairmentmentioning

confidence: 99%

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Bellesi

Conti

2010

Neuropsychopharmacol

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The main glutamate transporter GLT-1 is responsible for clearing synaptically released glutamate from the extracellular space and contributes to the shaping of glutamatergic transmission. Recently, it has been shown that ceftriaxone (CEF)-induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a simple form of information processing that is reduced in schizophrenia, and determines a strong reduction in hippocampal metabotropic glutamate receptor (mGluR)2/3-dependent long-term depression. In this study, we tested the hypothesis that administration of the mGluR2/3 agonist LY379268 blocks the effect of GLT-1 upregulation on PPI of the startle. We showed that administration of LY379268 (1 mg/kg) prevented PPI alterations associated with GLT-1 upregulation, suggesting that CEF-induced PPI impairment was mGluR2/3 dependent. In addition, we showed that CEF-induced GLT-1 upregulaton did not alter the expression of mGluR2/3, and also that it occurred at sites of mGluR2/3 expression. These results indicate a novel mechanism by which GLT-1 upregulation modulates PPI of the startle.

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Section: Ly379268 Blocks Cef-induced Ppi Impairmentmentioning

confidence: 99%

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Bellesi

Conti

2010

Neuropsychopharmacol

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“…The involvement of both dopamine receptors families with learning and memory is widely reported for working memory [3], spatial learning [3,6], aversive memory [7], reward-related learning [8] and cognitive flexibility [9]. In particular, impairment in object recognition has been induced by D2 activity suppression due to haloperidol IP injection [10], by D1 activity suppression trough http://dx…”

Section: H I G H L I G H T Smentioning

confidence: 99%

“…Furthermore, mice lacking D2 receptors do show memory consolidation deficits [15]. On the other hand, animals with high levels of synaptic DA, namely knockout mice for the DA transporter (DAT-KO), show impairment in the Morris water maze task [9], and also impairment of spatial memory in the Y-maze [16]. These animals presented, however, less immobility time in the forced swimming task [17], and exhibited an increase in locomotion, reversed by D2 receptor blocking [17].…”

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confidence: 99%

“…Based on the D2 influence on learning and memory [8][9][10], we used haloperidol to induce OR impairment. At the time point of 30 min before exploration (B.E.)…”

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confidence: 99%

“…DAT-KO mice also present deficits in odor recognition [13] and impairment in the normal wake-sleep cycle [25]. Using DAT-KO, Morice et al showed that these animals had impairment in the water-maze paradigm, and long-term depression [9]. In contrast, only a few studies have been published on DAT +/− mice, a mild model of hyperdopaminergia.…”

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Object recognition impairment and rescue by a dopamine D2 antagonist in hyperdopaminergic mice

França

Muratori

Nascimento

et al. 2016

Behavioural Brain Research

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h i g h l i g h t s• Heterozygous mice for dopamine transporter (DAT+/−) exhibit higher levels of synaptic dopamine.• Here we confirmed that D2 antagonism can interfere in object recognition.• We observed in DAT+/− a natural phenotype of impaired novel object memory recognition.• The injection of haloperidol at 0.05 mg before object exposition restored object recognition.• This effect could be explained by restoring D2 activity to optimal levels, acting on memory acquisition. a r t i c l e i n f o Genetically-modified mice without the dopamine transporter (DAT) are hyperdopaminergic, and serve as models for studies of addiction, mania and hyperactive disorders. Here we investigated the capacity for object recognition in mildly hyperdopaminergic mice heterozygous for DAT (DAT +/−), with synaptic dopaminergic levels situated between those shown by DAT −/− homozygous and wild-type (WT) mice. We used a classical dopamine D2 antagonist, haloperidol, to modulate the levels of dopaminergic transmission in a dose-dependent manner, before or after exploring novel objects. In comparison with WT mice, DAT +/− mice showed a deficit in object recognition upon subsequent testing 24 h later. This deficit was compensated by a single 0.05 mg/kg haloperidol injection 30 min before training. In all mice, a 0.3 mg/kg haloperidol injected immediately after training impaired object recognition. The results indicate that a mild enhancement of dopaminergic levels can be detrimental to object recognition, and that this deficit can be rescued by a low dose of a D2 dopamine receptor antagonist. This suggests that novel object recognition is optimal at intermediate levels of D2 receptor activity.© 2016 Elsevier B.V. All rights reserved.Dopamine (DA) is a neurotransmitter related to complex behaviors, such as: reward perception, social interaction [1,2], and is also linked to memory consolidation both in humans and rodents [3]. Alterations in DA synaptic regulation are related to a large variety of mental diseases, such as schizophrenia, hyperactivity, mood disorders, and Parkinson disease [4,5]. * Corresponding author.E-mail addresses: brunolobaosoares@gmail.com, brunolobaosoares@hotmail.com (B. Lobão-Soares).DA has many receptor subtypes, but they are basically divided in D1 and D2 families [3]. DA, mainly through D1 receptors, elicits the onset of the late phase of long term potentiation in the hippocampus [6], control plasticity-induced protein synthesis [6], and enhance the persistence of hippocampus-dependent memories [7].The involvement of both dopamine receptors families with learning and memory is widely reported for working memory [3], spatial learning [3,6], aversive memory [7], reward-related learning [8] and cognitive flexibility [9]. In particular, impairment in object recognition has been induced by D2 activity suppression due to haloperidol IP injection [10], by D1 activity suppression trough http://dx

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Interval‐timing Protocols and Their Relevancy to the Study of Temporal Cognition and Neurobehavioral Genetics

Yin

Lusk

Meck

2017

Handbook of Neurobehavioral Genetics and Phenotyping

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Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Cited by 102 publications

References 43 publications

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Object recognition impairment and rescue by a dopamine D2 antagonist in hyperdopaminergic mice

Interval‐timing Protocols and Their Relevancy to the Study of Temporal Cognition and Neurobehavioral Genetics

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