Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

Maiti, Panchanan; Manna, Jayeeta; Ilavazhagan, G.; Rossignol, Julien; Dunbar, Gary

doi:10.1016/j.neubiorev.2015.09.020

Cited by 100 publications

(95 citation statements)

References 347 publications

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“…These data agree well with the assumption that thin spines are involved in learning and that as this process gives way to storing of information, there is a reduction in the number of thin spines and a correlative increase in the population of mushroom spines. Such effects may be involved in enabling LTM (43,(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training

Bello-Medina

Flores

Quírarte

et al. 2016

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

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A growing body of evidence indicates that treatments that typically impair memory consolidation become ineffective when animals are given intense training. This effect has been obtained by treatments interfering with the neural activity of several brain structures, including the dorsal striatum. The mechanisms that mediate this phenomenon are unknown. One possibility is that intense training promotes the transfer of information derived from the enhanced training to a wider neuronal network. We now report that inhibitory avoidance (IA) induces mushroom spinogenesis in the medium spiny neurons (MSNs) of the dorsal striatum in rats, which is dependent upon the intensity of the foot-shock used for training; that is, the effect is seen only when high-intensity foot-shock is used in training. We also found that the relative density of thin spines was reduced. These changes were evident at 6 h after training and persisted for at least 24 h afterward. Importantly, foot-shock alone did not increase spinogenesis. Spine density in MSNs in the accumbens was also increased, but the increase did not correlate with the associative process involved in IA; rather, it resulted from the administration of the aversive stimulation alone. These findings suggest that mushroom spines of MSNs of the dorsal striatum receive afferent information that is involved in the integrative activity necessary for memory consolidation, and that intense training facilitates transfer of information from the dorsal striatum to other brain regions through augmented spinogenesis. A growing body of evidence indicates that treatments that commonly produce amnesia become ineffective when animals are given enhanced training (i.e., a high number of training sessions or relatively high levels of aversive stimulation). This protective effect against amnesia induced by interference with normal activity of brain nuclei has been found in a wide variety of learning tasks (1). Extensive evidence indicates that the dorsal striatum is intimately involved in the acquisition, consolidation, and retrieval memory for many kinds of training experiences (2-5). Interference with cholinergic activity of the dorsal striatum and reversible inactivation of this structure induced after moderate training impair memory consolidation. However, notably, these treatments are ineffective in impairing memory when animals are overtrained (6-10). Such findings suggest that intense training may induce functional changes within the dorsal striatum that prevent the impairment of memory. Although the dorsal striatum seems histologically homogeneous, there is a functional differentiation along its medial-lateral axis related to memory consolidation (11). Prior studies have shown that the dorsomedial striatum (DMS) is predominantly involved in spatial/contextual learning, influencing goal-directed behaviors (12, 13). In contrast, the dorsolateral striatum (DLS) enables the formation of procedural learning (4,14).Previous research suggests that memory consolidation may involve changes in the den...

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Section: Discussionmentioning

confidence: 99%

Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training

Bello-Medina

Flores

Quírarte

et al. 2016

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

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“…One dendrite per neuron was traced and the spines quantified and typified. Each spine was typified into one of four classes: thin, mushroom, stubby and branched (26).…”

Section: Golgi-cox Impregnation and Spine Analysismentioning

confidence: 99%

“…Dramatic changes in spine density and morphology in LID models has been previously demonstrated (22, 61). As Nurr1 is involved in learning and memory-associated plasticity classically associated with spine changes (32,34), we sought to determine if We next compared spine morphology, an indicator of synaptic strength and spine dynamics (26), between rAAV-Nurr1 and rAAV-GFP animals. We found that ectopic Nurr1 expression lead to a change in two specific spine phenotypes.…”

Section: Msn Spine Density and Morphology Changes Are Induced By Nurrmentioning

confidence: 99%

“…Some of these LID-associated changes in striatal plasticity are likely related to changes in dendritic spine morphology. Indeed, striatal spine density and morphology are dramatically altered in animal models following LID induction (22)(23)(24)(25)(26). These structural elements are dynamic, and their proliferation or pruning can occur due to normal neuronal processes such as motor learning or can be indicative of pathological states (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, striatal spine density and morphology are dramatically altered in animal models following LID induction (22)(23)(24)(25)(26). These structural elements are dynamic, and their proliferation or pruning can occur due to normal neuronal processes such as motor learning or can be indicative of pathological states (26)(27)(28). As in PD patients (29), animal models of PD have revealed dramatic spine loss following DA depletion, and in preclinical models, reestablishment of spine structure occurs with L-DOPA (22- 25,30,31).…”

Section: Introductionmentioning

confidence: 99%

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Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson’s Disease

Sellnow

Steece‐Collier

Altwal

et al. 2019

Preprint

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AbstractBackgroundThe transcription factor Nurr1 has been identified to be ectopically induced in the striatum of dyskinetic rodents expressing L-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression.MethodsWe used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with L-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single unit recordings and dendritic spine analyses in drug-naïve rAAV-injected parkinsonian rats.ResultsrAAV-GFP injected LID-resistant Lewis rats displayed mild LID and no induction of striatal Nurr1. However, Lewis rats transduced to overexpress Nurr1 developed severe LID. Nurr11 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in L-DOPA-naïve rats striatal rAAV-Nurr1 overexpression 1) increased firing activity in dopamine-depleted striatal direct pathway neurons, and 2) decreased spine density and thin-spine morphology on striatal medium spiny neurons, mimicking changes seen in dyskinetic rats. Finally, we provide post-mortem evidence of Nurr1 expression in the striatum of L-DOPA treated PD patients.ConclusionsOur data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

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A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

Tan

Gao

et al. 2023

Adv Healthcare Materials

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Ketamine (KA), commonly used as an anesthetic, is now widely studied as an antidepressant for the treatment of depression. However, due to its side effects, such as addiction and cognitive impairment, the dosage and frequency of (S)‐ketamine approved by the FDA for the treatment of refractory depression is very low, which limits its efficacy. Here, a new multifunctional nanocarrier system (AC‐RM@HA‐MS) with specific targeting capabilities is developed to improve the efficacy of KA treatment. KA‐loaded NPs (AC‐RM@HA‐MS‐KA) are constructed with a multilayer core–shell structure. KA‐loaded mesoporous silica NPs are prepared, conjugated with hyaluronic acid (HA) as pore gatekeepers, and sheathed with an RBC‐membrane (RM) for camouflage. Finally, the surface is tagged with bifunctional peptides (Ang‐2‐Con‐G, AC) to achieve specific targeting. One peptide (Ang‐2) is acted as a guide to facilitate the crossing of the blood–brain barrier (BBB), while the other (Con‐G) is functioned as a ligand for the targeted delivery of KA to the N‐methyl‐D‐aspartate receptor sites. Animal experiments reveal that AC‐RM@HA‐MS‐KA NPs effectively cross the BBB and directionally accumulate in the curing areas, thereby alleviating the depressive symptoms and improving the cognitive functions of depressed mice. After treatment, the depressed mice almost completely return to normal without obvious symptoms of addiction.

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Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

Cited by 100 publications

References 347 publications

Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training

Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training

Striatal Nurr1 Facilitates the Dyskinetic State and Exacerbates Levodopa-Induced Dyskinesia in a Rat Model of Parkinson’s Disease

A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

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