The reduced neuropil hypothesis: a circuit based model of schizophrenia

Selemon, Lynn D.; Goldman‐Rakic, Patricia S.

doi:10.1016/s0006-3223(98)00281-9

Cited by 840 publications

(517 citation statements)

References 79 publications

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“…A rich nomenclature has evolved around the general concept of functional synchrony of neural networks in schizophrenia. An inadequate amount of functional synchrony has been described from a variety of points of view as "disconnection syndrome," "reduced neuropil," "dysmetria," and "cortical oscillations" (Friston and Frith 1995;Friston 1998;Weinberger and Lipska 1995;Selemon and Goldman-Rakic 1999;Andreasen et al 1999;Fuster 1999;Green 1999).…”

Section: Myelination and Brain Functional Synchronymentioning

confidence: 99%

“…Compared with normal controls, individuals with schizophrenia seem to undergo an exaggerated reduction of gray matter volume in the context of minimal neuronal loss (Selemon and Goldman-Rakic 1999;McGlashan and Hoffman 2000;Woods 1998). The gray matter volume deficits observed in schizophrenia appear to be already present at the onset of the disease and to be non-progressive (Gur et al 2000a,b; for review see Pearlson and Marsh 1999).…”

Section: Myelination and Brain Functional Synchronymentioning

confidence: 99%

“…Considerable evidence indirectly supports a progressive loss of brain tissue volume occurring at some point during postnatal development. This evidence includes the larger extracerebral CSF volume with normal skull size in schizophrenia (as reviewed by Woods 1998), as well as postmortem evidence of decreased neuropil (as opposed to neurons themselves) in prefrontal, dorsolateral prefrontal, and occipital cortices (Selemon and Goldman-Rakic 1999;Uranova et al 2001;Cotter et al 2002). Longitudinal imaging studies comparing schizophrenic and control subjects age 10 or older have generally supported this hypothesis.…”

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confidence: 99%

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Schizophrenia Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

Bartzokis

2002

Neuropsychopharmacology

172

133

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Section: Myelination and Brain Functional Synchronymentioning

confidence: 99%

Section: Myelination and Brain Functional Synchronymentioning

confidence: 99%

mentioning

confidence: 99%

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Schizophrenia Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

Bartzokis

2002

Neuropsychopharmacology

172

133

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“…In schizophrenia, synaptic density is thought to be reduced in frontal cortex (Benes et al, 1991;Selemon et al, 1998;Selemon & Goldman-Rakic, 1999;Benes, 2000), while evidence for compromised inter-regional whitematter tracts is either lacking or inconsistent (McGuire & Frith, 1996).…”

Section: Model Accuracy and Dynamics After Gains Learningmentioning

confidence: 99%

Functional connectivity in fMRI: A modeling approach for estimation and for relating to local circuits

et al. 2007

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Although progress has been made in relating neuronal events to changes in brain metabolism and blood flow, the interpretation of functional neuroimaging data in terms of the underlying brain circuits is still poorly understood. Computational modeling of connection patterns both among and within regions can be helpful in this interpretation. We present a neural network model of the ventral visual pathway and its relevant functional connections. This includes a new learning method that adjusts the magnitude of interregional connections in order to match experimental results of an arbitrary functional magnetic resonance imaging (fMRI) data set. We demonstrate that this method finds the appropriate connection strengths when trained on a model system with known, randomly chosen connection weights. We then use the method for examining fMRI results from a one-back matching task in human subjects, both healthy and those with schizophrenia. The results discovered by the learning method support previous findings of a disconnection between left temporal and frontal cortices in the group with schizophrenia, and a concomitant increase of right-sided temporo-frontal connection strengths. We then demonstrate that the disconnection may be explained by reduced local recurrent circuitry in frontal cortex. This method extends currently available methods for estimating functional connectivity from human imaging data by including both local circuits and features of inter-regional connections, such as topography and sparseness, in addition to total connection strengths. Furthermore, our results suggest how fronto-temporal functional disconnection in schizophrenia can result from reduced local synaptic connections within frontal cortex rather than compromised inter-regional connections.

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“…Alterations in synaptic proteins and their encoding mRNAs are reported in several brain areas including the prefrontal cortex of schizophrenic patients in the absence of gross structural abnormalities (Selemon and Goldman-Rakic 1999). The emerging picture of neuropathology in schizophrenia is one of subtle changes in cellular architecture and brain circuity (Lieberman et al 1997) that nonetheless may have a devastating impact on cortical function.…”

Section: Neurochemical Measuresmentioning

confidence: 99%

Further Evidence that Behavioral Tests and Neuropeptide mRNA and Tissue Level Alterations Can Differentiate between Typical and Atypical Antipsychotic Drugs

Bauer

Mayr

Lederer

et al. 2000

Neuropsychopharmacology

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This study was designed to compare some behavioral and biochemical effects of chronic treatment with a range of antipsychotic drugs. Gene expression of enkephalinAntipsychotic drugs are sometimes referred to as "atypical" if they demonstrate the ability to produce an antipsychotic action in most patients but with significantly less extrapyramidal side effects than classical (typical) antipsychotics (Fleischhacker and Hummer 1997). Lately, this distinction between "typical" and "atypical" antipsychotics has become the focus for much research aimed at establishing the pharmacological characteristics that serve to distinguish atypical antipsychotic drugs from the typical ones (Arnt and Skarsfeldt 1998). For example, in animals, acute and chronic treatment with these compounds causes distinct behavioral changes and alterations in the expression of different genes.Alterations in the biosynthesis of synaptic proteins and their mRNAs can be used to investigate changes in neuronal activity following different neuronal stimuli (MacArthur and Eiden 1996). Haloperidol increases tissue levels of enkephalin and the expression of mRNA (Normand et al. 1987;Romano et al. 1987) in medium spiny striatal neurons which are associated with the dopamine 2 receptor (Le Moine et al. 1991) whereas clozapine, the prototypical "atypical" antipsychotic, does not induce catalepsy and does not lead to an increased enkephalin gene expression in the striatum (Mercugliano and Chesselet 1992). Consequently, antipsychotics which do not induce catalepsy appear unlikely to increase enkephalin biosynthesis (Augood et al. 1993;Mijnster et al. 1998). Therefore, both behavioral changes and a distinct pattern of gene expression may be used to predict an atypical profile for an antipsychotic compound.The prefrontal cortex is an important brain area in schizophrenia research (Knable and Weinberger 1997;O'Donnell and Grace 1998). In animals, antipsychotic treatment causes an induction of immediate early genes in various brain areas including the prefrontal cortex. In this region, acute application of haloperidol or clozapine induces a differential expression of immediate early genes (Nguyen et al. 1992;Robertson and Fibiger 1992;Deutch and Duman 1996). Therefore, a different mechanism of action was postulated for haloperidol or clozapine treatment. However, most of these experiments investigated the induction of early genes after acute treatment.Chromogranin A, chromogranin B, and secretogranin II belong to the chromogranin family which are large protein molecules found in large dense core vesicles. They are endoproteolytically processed to smaller peptides, and are released after neuronal stimulation (Huttner et al. 1991). The distribution of chromogranin B (Mahata et al. 1991;Kroesen et al. 1996), secretogranin II mRNA, and their immunoreactivity (Marksteiner et al. 1993a) have been studied in rat brains. The biosynthesis of chromogranins is regulated by different stimuli (Shen and Gundlach 1996). For example, ten days of treatment with clozapine or hal...

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The reduced neuropil hypothesis: a circuit based model of schizophrenia

Cited by 840 publications

References 79 publications

Schizophrenia Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

Schizophrenia Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

Functional connectivity in fMRI: A modeling approach for estimation and for relating to local circuits

Further Evidence that Behavioral Tests and Neuropeptide mRNA and Tissue Level Alterations Can Differentiate between Typical and Atypical Antipsychotic Drugs

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