Ketamine-related expression of glutamatergic postsynaptic density genes: Possible implications in psychosis

Iasevoli, Felice; Polese, Daniela; Ambesi-Impiombato, Alberto; Muscettola, Giovanni; Bartolomeis, Andrea de

doi:10.1016/j.neulet.2007.01.041

Cited by 36 publications

(17 citation statements)

References 35 publications

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“…This finding is surprising as previous studies suggest numerous changes in gene expression during acute ketamine psychosis. [71][72][73] The small number of significant changes was not due to variations among the animals, because the 2D gel electrophoresis analyses were highly reproducible between all eight samples in each group. Previous work suggests that the mammalian postsynaptic proteome consists of a highly interconnected set of approximately more than 1000 proteins.…”

Section: Discussionsupporting

confidence: 93%

A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia

et al. 2008

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Section: Discussionsupporting

confidence: 93%

A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia

et al. 2008

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“…The induction of Homer1a has been extensively investigated in vitro including neuronal depolarization with ionotropic glutamate receptor agonists, N-methyl-D-aspartate (NMDA), kainite, and potassium channel blockers [31], application of brain-derived neurotrophic factor (BDNF) [42], traumatic injury [43, 44], and evoking epileptiform activity with bicuculline and 4-aminopyridine [45]. Meanwhile the induction of Homer1a in vivo has been reported following electroconvulsive shock [6, 7, 11, 46], long-term potentiation (LTP) [27, 46], exposure to psychoactive drugs such as cocaine [7, 40], lysergic acid diethylamide [47, 48], and NMDA receptor antagonist ketamine [49, 50], direct dopamine D1 receptor stimulation [12], typical and atypical antipsychotic administration [36, 37, 51, 52], Pavlovian fear conditioning [16, 42], instrumental learning [53], exploration of a novel environment [16, 38, 54], running [55], visual experience [7], environmental stressors [39, 56], and neuropathic pain [57]. Importantly, it is exclusively the short, IEG isoforms of the Homer1 gene that are induced under these conditions, while the expression of the longer isoforms typically remains unchanged.…”

Section: Homer1 Ieg Induction and Regulationmentioning

confidence: 97%

“…This response is necessary for the regulation of cocaine sensitivity [123, 158]. Psychotomimetic NMDA receptor antagonists such as ketamine and MK-801 are thought to model some aspects of schizophrenia pathology and induce Homer1a expression [49, 50], while antipsychotics such as haloperidol and clozapine also modulate Homer1a [36, 37, 52, 159, 160] and Ania-3 expression [160]. …”

Section: Implications For Psychiatric Disordersmentioning

confidence: 99%

Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

et al. 2019

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Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders.

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“…6 In agreement with this finding is evidence for an increased expression of the excitatory PSD protein SAP90/PSD-95-associated protein 1 (SAPAP1) in the NAcc in postmortem SZ. 23 Rodent models of SZ also exhibit increased indices of glutamatergic-type input in the NAcc; rats treated with psychotomimetics have increased mRNA expression of excitatory PSD genes, 23,24 and increased dendritic spine density in the NAcc, [25][26][27] which is tightly correlated with the density of AS synapses. 28 A likely source of this elevated input in SZ and its functional implications are discussed below.…”

Section: Elevated Excitatory Input In Szmentioning

confidence: 99%

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

McCollum

Walker

Roche

et al. 2015

SCHBUL

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The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

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Ketamine-related expression of glutamatergic postsynaptic density genes: Possible implications in psychosis

Cited by 36 publications

References 35 publications

A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia

A comparison of the synaptic proteome in human chronic schizophrenia and rat ketamine psychosis suggest that prohibitin is involved in the synaptic pathology of schizophrenia

Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

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