Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence?

Feinberg, Irwin

doi:10.1016/0022-3956(82)90038-3

Cited by 1,278 publications

(712 citation statements)

References 25 publications

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“…For example, the expression of NCAM PSA is reduced in the hippocampal dentate of schizophrenic patients suggestive of a deficit in memory associated synaptic plasticity mechanisms (Barbeau et al, 1995). Thus, the benefits accruing from such procognitive interventions have the potential to oppose and even reverse aberrant synaptic connectivity patterning that likely underlie the developmental emergence of disorders such as autism, schizophrenia, and Alzheimer's disease (Braak and Braak, 1991;Bobinski et al, 1995;Scheff et al, 1996;Feinberg, 1982;Hoffman and McGlashan, 1997;Mirnics et al, 2001;Volkmar and Pauls, 2003).…”

Section: Discussionmentioning

confidence: 99%

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Murphy

Foley

O’Connell

et al. 2005

Neuropsychopharmacol

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Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a diseasemodifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memoryassociated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Murphy

Foley

O’Connell

et al. 2005

Neuropsychopharmacol

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“…The profound reorganization of synaptic activity that occurs during adolescence could be responsible for the significant reductions in phase synchronization observed. The emergence of psychotic symptoms in schizophrenia during late adolescence/early adulthood could be a consequence of this reorganization process in compromised inhibitory networks (Feinberg 1982).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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“…For example, with reference to the pruning hypothesis (Feinberg, 1982;Saugstad, 1994;Siekmeier and Hoffman, 2002), the pruning effects that we found with our computer simulations could thus point at a shift in the balance between stability and flexibility of the neural networks of the brain, that possibly could be reflected in a similar shift at a cognitive/mental level. It is also conceivable that a suboptimal timing of the extensive pruning process that occurs during development could well have an effect on the stability-flexibility balance of the mental processes in later stages of life.…”

Section: Discussionmentioning

confidence: 73%

“…In particular, we show (1) how a complex neurodynamics can provide both flexibility and stability for the system and (2) how this neurodynamics can be regulated by means of neuromodulators (such as acetylcholine (ACh)) and noise, in order to change system sensitivity and response rapidness. We also investigate (3) how the network connectivity is linked to its dynamics and learning capacities, and what effects synaptic modification and pruning may have on the balance between stability and flexibility, relating to the pruning hypothesis (Feinberg, 1982;Saugstad, 1994;Siekmeier and Hoffman, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…For example, it has been hypothesized (Feinberg, 1982;Saugstad, 1994;Siekmeier and Hoffman, 2002) that mental disorders might be connected to the pruning of the neural networks of the developing brain. The idea is briefly the following: during initial development, a neural system generally overproduces many structural elements such as neurons, dendrites, axons, and synapses.…”

Section: Introductionmentioning

confidence: 99%

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Neural Stability and Flexibility: A Computational Approach

Liljenström¹

2003

Neuropsychopharmacol

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This paper addresses the issue of stability and flexibility of neural systems, and how a balance can be achieved. Assuming a close correspondence with cognitive and mental processes, we use a cortical neural network model to investigate how regulation of the neurodynamics can result in an efficient information processing, in terms of learning and associative memory. In particular, we use this model to investigate relations between structure, dynamics, and function of a neural system, and how the stability-flexibility dilemma may be solved by proper regulation. We focus on the complex neurodynamics and its modulation, and how this is related to the neural circuitry, where synaptic modification and network pruning are considered. Finally, we discuss the relevance of these results to clinical and experimental neuroscience and speculate on a link between neural instability and mental disorders.

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Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence?

Cited by 1,278 publications

References 25 publications

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

Neural Stability and Flexibility: A Computational Approach

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