Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

doi:10.1016/j.biopsych.2017.01.004

Biological Psychiatry

Volume 81, Issue 10, 15 May 2017, Pages 874-885

https://doi.org/10.1016/j.biopsych.2017.01.004 Get rights and content

Abstract

The functional optimization of neural ensembles is central to human higher cognitive functions. When the functions through which neural activity is tuned fail to develop or break down, symptoms and cognitive impairments arise. This review considers ways in which disturbances in the balance of excitation and inhibition might develop and be expressed in cortical networks in association with schizophrenia. This presentation is framed within a developmental perspective that begins with disturbances in glutamate synaptic development in utero. It considers developmental correlates and consequences, including compensatory mechanisms that increase intrinsic excitability or reduce inhibitory tone. It also considers the possibility that these homeostatic increases in excitability have potential negative functional and structural consequences. These negative functional consequences of disinhibition may include reduced working memory–related cortical activity associated with the downslope of the “inverted-U” input–output curve, impaired spatial tuning of neural activity and impaired sparse coding of information, and deficits in the temporal tuning of neural activity and its implication for neural codes. The review concludes by considering the functional significance of noisy activity for neural network function. The presentation draws on computational neuroscience and pharmacologic and genetic studies in animals and humans, particularly those involving N-methyl-D-aspartate glutamate receptor antagonists, to illustrate principles of network regulation that give rise to features of neural dysfunction associated with schizophrenia. While this presentation focuses on schizophrenia, the general principles outlined in the review may have broad implications for considering disturbances in the regulation of neural ensembles in psychiatric disorders.

Section snippets

Excitatory synaptic deficits

Schizophrenia, at its developmental core, is a disorder of E/I imbalance arising from deficient excitatory connectivity. The symptoms of schizophrenia, particularly the prominent cognitive and negative symptoms, are associated with reductions in cortical gray matter (6) and white matter (7) and with reduced task-related prefrontal cortical activation, although not universally so (8).

Deficits in glutamate synaptic structure and function are a component of the neurobiology of schizophrenia (9).

Impaired tuning of the magnitude of excitation, allostatic adaptations, and the inverted U

There is also evidence of increased excitability or cortical disinhibition in schizophrenia, particularly early in the course of illness. For example, cortical levels of glutamate, glutamine, and GABA as measured by ¹H magnetic resonance spectroscopy are elevated in healthy individuals at high genetic risk or in patients early in their course of illness, with declining levels with advancing age to a point below that of healthy subjects (24, 25, 26, 27, 28, 29, 30). In addition, studies of

Deficits in spatial tuning of cortical activity and impairments in sparse coding

The representation of information by the cortex requires fine-grained tuning of the spatial dispersion of excitation within a localized area. Within the primate prefrontal cortex, the representation of particular spatial locations within spatial working memory depends on the selective activation of particular layer 3 neurons and their associated microcolumns as well as the interneuron-mediated inhibition of neighboring neurons and microcolumns representing competing locations (87, 88). The

Deficits in temporal tuning of cortical activity: ensembles, oscillations, and codes

The neural representation of information is a property of the coordinated activity of assemblies (97, 113). Exactly how the brain accomplishes this task is somewhat of a mystery. A focus on individual cortical neurons has provided critical insights into working memory and other cognitive functions (114). However, it is likely that functional connectivity within ensembles is reflected in higher order properties of neural networks, such as oscillations in network activity, because the activities

Tuning Deficits, Signals, and Noise

Tuning deficits associated with schizophrenia reduce the ability of neural assemblies to represent information, that is, to generate signals. This review has considered the impact of deficiencies in several forms of the tuning of neural activity among cortical network functions, that is, activation level, spatial extent of activation, and timing of activation. Each of these deficits contributed to reductions in signal integrity. Consistent with the inverted-U input–output relationship (Figure 2

Conclusions

Disturbances in the signal representation and information processing properties of the cerebral cortex appear to be a proximal cause of symptoms and functional impairments associated with schizophrenia and perhaps other forms of psychopathology. This review highlighted ways in which impairments in the tuning properties of cortical networks related to E/I imbalances could arise from signaling abnormalities within cortical microcircuits and then contribute to disturbances in the functional

Acknowledgments and Disclosures

This paper was supported primarily by the National Center for Advancing Translational Science (Grant No. 1UH2TR000960-01). Yale Center for Clinical Investigation supports work from JHK, AA, and NRD. Additional support came from the National Institute on Alcohol Abuse and Alcoholism (Grant No. P50AA12870 to JHK), the Yale Center for Clinical Investigation (Grant No. UL1 RR024139), and the Department of Veterans Affairs through its support for the Veterans Affairs National Center for PTSD (to

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ReviewImpaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

Abstract

Section snippets

Excitatory synaptic deficits

Impaired tuning of the magnitude of excitation, allostatic adaptations, and the inverted U

Deficits in spatial tuning of cortical activity and impairments in sparse coding

Deficits in temporal tuning of cortical activity: ensembles, oscillations, and codes

Tuning Deficits, Signals, and Noise

Conclusions

Acknowledgments and Disclosures

Brain Res Rev

Biol Psychiatry

Am J Hum Genet

Biol Psychiatry

Cell

Biol Psychiatry

Neuron

Neuroimage Clin

Schizophr Res

Biol Psychiatry

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Neuron

Biol Psychiatry

Neuron

Biol Psychiatry

Curr Opin Neurobiol

Biol Psychiatry

Neuron

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Prog Mol Biol Transl Sci

Schizophr Res

Biol Psychiatry

Trends Neurosci

Neuron

Neuron

Neuron

Clinical heterogeneity arising from categorical and dimensional features of the neurobiology of psychiatric diagnoses: Insights from neuroimaging and computational neuroscience

Molecular mechanisms of epilepsy

Nat Neurosci

Excitatory/inhibitory imbalance in autism spectrum disorders: Implications for interventions and therapeutics

World J Biol Psychiatry

Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies

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Rethinking schizophrenia in the context of normal neurodevelopment

Front Cell Neurosci

Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families

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Schizophrenia risk from complex variation of complement component 4

Nature

(2014): Biological insights from 108 schizophrenia-associated genetic loci

Nature

Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes

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Layer 3 excitatory and inhibitory circuitry in the prefrontal cortex: Developmental trajectories and alterations in schizophrenia [published online ahead of print Jun 4]

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GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression

J Neurosci

Medial frontal GABA is lower in older schizophrenia: A MEGA-PRESS with macromolecule suppression study

Mol Psychiatry

Review
Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

Glutamate in schizophrenia: A focused review and meta-analysis of ¹H-MRS studies