Neural Circuitry of the Prefrontal Cortex in Schizophrenia

Lewis, David A.

doi:10.1001/archpsyc.1995.03950160019004

Cited by 50 publications

(40 citation statements)

References 62 publications

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“…Impaired cognitive functioning is a fundamental feature of schizophrenia, and impoverished executive abilities contribute to the poor functional outcome of patients (Ragland et al 2007). Numerous studies indicate that dysfunction of the dlPFC underlies schizophrenia pathophysiology (e.g., Goldman-Rakic 1994, 1995aLewis 1995;Lewis and Anderson 1995;GoldmanRakic and Selemon 1997;Glantz and Lewis 2000). Early studies by Weinberger and colleagues using the Wisconsin Card Sorting Task (WCST), which measures concept formation, working memory, cognitive flexibility, and feedback monitoring, found reduced cerebral blood flow to the dlPFC in schizophrenia patients compared with healthy control subjects Weinberger et al 1986Weinberger et al , 1988.…”

Section: Schizophreniamentioning

confidence: 99%

“…Disturbances in prefrontal cortex (PFC) are evident in numerous neuropsychiatric illnesses including bipolar disorder (e.g., Blumberg et al 1999Blumberg et al , 2002Glahn et al 2006), schizophrenia (e.g., Goldman-Rakic 1994; Lewis 1995), and Post-Traumatic Stress Disorder (PTSD) (e.g., Bremner et al 1995;Southwick et al 1997;Shin et al 2006). Functional and morphological weaknesses in PFC have been linked to cognitive deficits that underlie many of the most debilitating symptoms of these disorders.…”

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confidence: 99%

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Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

Hains¹,

Arnsten²

2008

Learn. Mem.

113

102

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The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of α1 receptors impairs prefrontal function via phosphatidylinositol–protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)—the molecule most associated with bipolar disorder— normally serve to inhibit phosphatidylinositol–protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.

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Section: Schizophreniamentioning

confidence: 99%

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confidence: 99%

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

Hains¹,

Arnsten²

2008

Learn. Mem.

113

102

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“…1A). Deep layer pyramidal cells are the ones most strongly innervated by dopaminergic fibers in the rat and primate PFC and express the highest levels of mRNA for all DA receptor subtypes (Berger et al 1988(Berger et al , 1991Goldman-Rakic et al 1992;Joyce et al 1993;Lewis et al 1992;Lidow et al 1998). Furthermore they constitute the major portion of neurons exhibiting sustained delay activity (Fuster 1973).…”

Section: Pyramidal Cell Modelmentioning

confidence: 99%

Dopamine-Mediated Stabilization of Delay-Period Activity in a Network Model of Prefrontal Cortex

Durstewitz

Seamans

Sejnowski

2000

Journal of Neurophysiology

555

412

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jnowski. Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J. Neurophysiol. 83: 1733Neurophysiol. 83: -1750Neurophysiol. 83: , 2000. The prefrontal cortex (PFC) is critically involved in working memory, which underlies memory-guided, goal-directed behavior. During working-memory tasks, PFC neurons exhibit sustained elevated activity, which may reflect the active holding of goal-related information or the preparation of forthcoming actions. Dopamine via the D1 receptor strongly modulates both this sustained (delay-period) activity and behavioral performance in working-memory tasks. However, the function of dopamine during delay-period activity and the underlying neural mechanisms are only poorly understood. Recently we proposed that dopamine might stabilize active neural representations in PFC circuits during tasks involving working memory and render them robust against interfering stimuli and noise. To further test this idea and to examine the dopamine-modulated ionic currents that could give rise to increased stability of neural representations, we developed a network model of the PFC consisting of multicompartment neurons equipped with Hodgkin-Huxley-like channel kinetics that could reproduce in vitro whole cell and in vivo recordings from PFC neurons. Dopaminergic effects on intrinsic ionic and synaptic conductances were implemented in the model based on in vitro data. Simulated dopamine strongly enhanced high, delay-type activity but not low, spontaneous activity in the model network. Furthermore the strength of an afferent stimulation needed to disrupt delay-type activity increased with the magnitude of the dopamine-induced shifts in network parameters, making the currently active representation much more stable. Stability could be increased by dopamine-induced enhancements of the persistent Na ϩ and N-methyl-D-aspartate (NMDA) conductances. Stability also was enhanced by a reduction in AMPA conductances. The increase in GABA A conductances that occurs after stimulation of dopaminergic D1 receptors was necessary in this context to prevent uncontrolled, spontaneous switches into high-activity states (i.e., spontaneous activation of task-irrelevant representations).In conclusion, the dopamine-induced changes in the biophysical properties of intrinsic ionic and synaptic conductances conjointly acted to highly increase stability of activated representations in PFC networks and at the same time retain control over network behavior and thus preserve its ability to adequately respond to task-related stimuli. Predictions of the model can be tested in vivo by locally applying specific D1 receptor, NMDA, or GABA A antagonists while recording from PFC neurons in delayed reaction-type tasks with interfering stimuli.

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“…Layer III pyramidal cells provide reciprocal connections with other cortical regions (Lewis, 1995;Lewis and Anderson, 1995) as well as intrinsic circuitry within the DLPFC, wherein these cells provide local and long-range axon collaterals that arborize in stripe-like clusters (Levitt et al, 1993;Lewis et al, 2003;Pucak et al, 1996). Long-range collaterals target dendritic spines of other pyramidal cells, while local axon collaterals target both the dendritic shaft of parvalbumincontaining interneurons and dendritic spines of pyramidal cells Melchitzky and Lewis, 2003;Melchitzky et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Converging evidence from human postmortem, neuropsychological and imaging studies implicate the dorsolateral prefrontal cortex (DLPFC) as an important brain region in schizophrenia (Bunney and Bunney, 2000;Callicott et al, 2000;Castner et al, 2004;Goldman-Rakic, 1994;Goldman-Rakic and Selemon, 1997;Lewis, 1995;Weinberger et al, 1994;Weinberger et al, 1986). Cognitive dysfunction is a defining feature of schizophrenia (Goldberg et al, 1993;Harvey et al, 2001;Weinberger and Gallhofer, 1997) and is associated with deficits in DLPFC functioning (Goldman-Rakic, 1994; Goldman-Rakic and Selemon, 1997;Lewis and Gonzalez-Burgos, 2000;Weinberger et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia

O’Connor

Hemby

2007

Schizophrenia Research

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The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/ group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology.

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Neural Circuitry of the Prefrontal Cortex in Schizophrenia

Cited by 50 publications

References 62 publications

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

Dopamine-Mediated Stabilization of Delay-Period Activity in a Network Model of Prefrontal Cortex

Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia

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