Differentiation of forebrain and hippocampal dopamine 1-class receptors, D1R and D5R, in spatial learning and memory

Sariñana, Joshua; Tonegawa, Susumu

doi:10.1002/hipo.22492

Cited by 21 publications

(16 citation statements)

References 55 publications

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“…Startle response and pre-pulse inhibition are normal in these mice. Memory assessing paradigms (Morris water maze, and cued and contextual fear conditioning) are also not altered 17,21 , however, when probed more thoroughly, such as for example in a paired-trial T-maze test and a temporal order object recognition task, the KO mice exhibited reduced performance 22 .…”

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confidence: 95%

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Castello

Cortés

Malave

et al. 2020

Sci Rep

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The dopamine D5 receptor (D5R) is a Gα s-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, it affects up to 4% of people aged 65 years or more 1. Hallmarks of the disorder are motor symptoms such as tremor, rigidity, bradykinesia and gait disturbances 2 , which are a result of the selective degeneration of dopaminergic neurons within the substantia nigra pars compacta and thus not by but of dopamine depletion 3. Up to today, L-DOPA treatment remains the gold standard treatment for PD. In the majority of patients, the efficacy of L-DOPA is reduced and debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), develop during chronic L-DOPA treatment over several years 4. Various pharmacological tools are currently investigated with the aim to mitigate these complications. The striatum is comprised mainly by two types of GABAergic projection neurons (SPNs) that are categorized based on their predominant expression of either D1-or D2 receptors, together making up over 95% of all striatal neurons 5. The spiny neurons that project directly to the basal ganglia output nuclei are termed 'direct pathway' or dSPNs and express D1 receptor (D1R), that signals via the G proteins Gα s /Gα olf to PKA and enhances cAMP production. The other class of projection neurons is termed 'indirect pathway' or iSPNs, and they express the inhibitory, Gα i/o-coupled D2 receptor (D2R) 6 , leading to less cAMP being produced. The balance between the two pathways is crucial for voluntary movement control and is disturbed in PD. In addition, cholinergic interneurons (CINs), which represent 1-3% of striatal neurons but are extensively arborized, gat...

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confidence: 95%

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Castello

Cortés

Malave

et al. 2020

Sci Rep

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“…In mammals many studies have shown a prominent role of dopamine signalling in hippocampal-dependent memory tasks including LTM 48 49 , through D1-class receptors 50 51 52 , but without discriminating the involvement of D1 or D5 receptors. A couple of recent reports have started to investigate the role of either receptor type separately, revealing that both may actually be involved, but their respective functional roles remains to be clarified 52 53 54 .…”

Section: Discussionmentioning

confidence: 99%

Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory

et al. 2017

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Efficient energy use has constrained the evolution of nervous systems. However, it is unresolved whether energy metabolism may resultantly regulate major brain functions. Our observation that Drosophila flies double their sucrose intake at an early stage of long-term memory formation initiated the investigation of how energy metabolism intervenes in this process. Cellular-resolution imaging of energy metabolism reveals a concurrent elevation of energy consumption in neurons of the mushroom body, the fly's major memory centre. Strikingly, upregulation of mushroom body energy flux is both necessary and sufficient to drive long-term memory formation. This effect is triggered by a specific pair of dopaminergic neurons afferent to the mushroom bodies, via the D5-like DAMB dopamine receptor. Hence, dopamine signalling mediates an energy switch in the mushroom body that controls long-term memory encoding. Our data thus point to an instructional role for energy flux in the execution of demanding higher brain functions.

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“…Although we did not perform direct comparisons between the DH and RSC (because the experiments were performed separately, at different times, and in different behavioral rooms, resulting in different freezing levels in vehicle controls), the observed effects point toward a model of muscarinic contribution to retrieval that is multifaceted and non-uniform across brain regions. Unlike other neurotransmitter receptors such as NMDAR (Gao et al 2010), AMPA receptors (Schiapparelli et al 2006;Bannerman 2009), adrenergic receptors (Gibbs and Summers 2002;Galeotti et al 2004), and dopamine receptors (Sarinana et al 2014;Sarinana and Tonegawa 2016) for which the roles of specific receptor subunits or subtypes are clearly discriminable in various memory processes, it seems that activation of several mAChR subtypes may be necessary to maximally effect one process. This model is consistent with findings using electrophysiological approaches, which demonstrate that cortical M 1 , M 2 , and M 4 together exert a "triad of effects" (M 1 increases neuronal firing rates, M 2 mediates a decrease in cellular inhibition, and M 4 depresses excitatory transmission), which may underlie attention and learning (Gigout et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

et al. 2016

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Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing. Using pharmacological and genetic approaches, we found that (1) encoding and retrieval of contextual memory requires mAChR in the dorsal hippocampus (DH) and retrosplenial cortex (RSC), (2) memory formation requires hippocampal M 3 and cooperative activity of RSC M 1 and M 3, and (3) memory retrieval is more impaired by inactivation of multiple M 1 -M 4 mAChR in DH or RSC than inactivation of individual receptor subtypes. Contrary to the view that acetylcholine supports learning but is detrimental to memory retrieval, we found that coactivation of multiple mAChR is required for retrieval of both recently and remotely acquired context memories. Manipulations with higher receptor specificity were generally less potent than manipulations targeting multiple receptor subtypes, suggesting that mAChR act in synergy to regulate memory processes. These findings provide unique insight into the development of therapies for amnestic symptoms, suggesting that broadly acting, rather than receptor-specific, mAchR agonists and positive allosteric modulators may be the most effective therapeutic approach.

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Differentiation of forebrain and hippocampal dopamine 1-class receptors, D1R and D5R, in spatial learning and memory

Cited by 21 publications

References 55 publications

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

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