Postnatal Development of Prefrontal Inhibitory Circuits and the Pathophysiology of Cognitive Dysfunction in Schizophrenia

Lewis, David A.; Cruz, Dianne A.; Eggan, Stephen M.; Erickson, Susan

doi:10.1196/annals.1308.008

Cited by 112 publications

(84 citation statements)

References 70 publications

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“…In the DLFPC of individuals with schizophrenia, a pathogenic shift in ErbB4 splicing from the JM-b to JM-a variants has been associated with fewer excitatory synaptic inputs to PV interneurons (26,28), which could reflect an exaggerated pruning process in these neurons. Therefore, findings from our study support the view that schizophrenia is a neurodevelopmental disorder with disturbances in the normal maturation process of prefrontal inhibitory circuits (59).…”

Section: Phospho-erbb4supporting

confidence: 78%

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Chung

Wills

Fish

et al. 2017

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

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Working memory requires efficient excitatory drive to parvalbuminpositive (PV) interneurons in the primate dorsolateral prefrontal cortex (DLPFC). Developmental pruning eliminates superfluous excitatory inputs, suggesting that working memory maturation during adolescence requires pruning of excitatory inputs to PV interneurons. Therefore, we tested the hypothesis that excitatory synapses on PV interneurons are pruned during adolescence. The density of excitatory synapses, defined by overlapping vesicular glutamate transporter 1-positive (VGlut1+) and postsynaptic density 95-positive (PSD95+) puncta, on PV interneurons was lower in postpubertal relative to prepubertal monkeys. In contrast, puncta levels of VGlut1 and PSD95 proteins were higher in postpubertal monkeys and positively predicted activity-dependent PV levels, suggesting a greater strength of the remaining synapses after pruning. Because excitatory synapse number on PV interneurons is regulated by erb-b2 receptor tyrosine kinase 4 (ErbB4), whose function is influenced by alternative splicing, we tested the hypothesis that pruning of excitatory synapses on PV interneurons is associated with developmental shifts in ErbB4 expression and/or splicing. Pan-ErbB4 expression did not change, whereas the minor-to-major splice variant ratios increased with age. In cell culture, the major, but not the minor, variant increased excitatory synapse number on PV interneurons and displayed greater kinase activity than the minor variant, suggesting that the effect of ErbB4 signaling in PV interneurons is mediated by alternative splicing. Supporting this interpretation, in monkey DLPFC, higher minor-to-major variant ratios predicted lower PSD95+ puncta density on PV interneurons. Together, our findings suggest that ErbB4 splicing may regulate the pruning of excitatory synapses on PV interneurons during adolescence.synaptic pruning | parvalbumin interneuron | ErbB4 | alternative splicing | schizophrenia I n primates, certain complex cognitive processes, such as working memory, depend in part on the proper activation of specific neural circuits in the dorsolateral prefrontal cortex (DLPFC) (1). In both monkeys and humans, recruitment of DLPFC activity and performance during working memory tasks continue to improve through adolescence (2-4). During this period, excitatory synapses and their principal targets, pyramidal neuron dendritic spines, massively decline in number in the primate DLPFC (5-8). Synaptic pruning is thought to eliminate unwanted or imprecise connections and to strengthen the remaining connections (9, 10), suggesting that this process could contribute to the maturation of working memory function during adolescence.Working memory is thought to emerge from oscillatory activity of DLPFC neurons at gamma frequency (30-80 Hz) (11), which requires the activity of local GABAergic interneurons that express the calcium binding protein parvalbumin (PV) (12, 13). During working memory tasks, excitation from pyramidal neurons recruits PV interneurons, which in turn pro...

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Section: Phospho-erbb4supporting

confidence: 78%

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Chung

Wills

Fish

et al. 2017

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

Self Cite

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“…In rodents and primates, maturation of the PV-interneuronal system occurs postnatally (reviewed in (Lewis et al, 2004;Huang, 2009)). Studies performed in rodents show that migration from the medial ganglionic eminence to the cortical plate is complete by around embryonic day 15, but the neurons remain silent until the beginning of the second postnatal week when their maturation begins.…”

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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“…Relatively recent work in animals suggests that structural and functional connectivity among these neural systems evolve during adolescence (Cunningham et al 2002; see reviews, Lewis, 1997;Lewis et al 2004). For example, amygdalo-cortical fibers become denser throughout adolescence in the rodent, perhaps reflecting the development of better regulatory controls with respect to harm-avoidant behavior (Cunningham et al 2002).…”

Section: Neural Maturation and Connectivity In Support Of The Triadicmentioning

confidence: 99%

“…At the same time, preliminary findings in the non-human primate indicate reduction in dendritic branching in the medial amygdala in adolescence (J. L. Zehr, unpublished observations). Findings in adolescent monkeys show marked changes of pre-and post-synaptic markers of GABA neurotransmission in the prefrontal cortex during adolescence, suggesting continued maturation of inhibitory controls (Lewis et al 2004). …”

Section: Neural Maturation and Connectivity In Support Of The Triadicmentioning

confidence: 99%

Triadic model of the neurobiology of motivated behavior in adolescence

2005

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Postnatal Development of Prefrontal Inhibitory Circuits and the Pathophysiology of Cognitive Dysfunction in Schizophrenia

Cited by 112 publications

References 70 publications

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

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

Triadic model of the neurobiology of motivated behavior in adolescence

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