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Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance

Research output: Contribution to journalReview articlepeer-review

Oliver D. Howes, Ekaterina Shatalina

Original languageEnglish
Pages (from-to)501-513
Number of pages13
JournalBiological psychiatry
Issue number6
Early online date22 Aug 2022
Accepted/In press4 Jun 2022
E-pub ahead of print22 Aug 2022
Published15 Sep 2022

Bibliographical note

Funding Information: We thank Dr. Robert McCutcheon for his critical reading of the manuscript. ODH is a part-time employee of H Lundbeck A/S. He has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche, and Viatris/Mylan. Neither ODH nor his family have holdings/a financial stake in any pharmaceutical company. ODH has a patent for the use of dopaminergic imaging. ES reports no biomedical financial interests or potential conflicts of interest. The views expressed are those of the authors and not necessarily those of H Lundbeck A/s, the NHS/NIHR, or the Department of Health. Publisher Copyright: © 2022 Society of Biological Psychiatry


King's Authors


The neurodevelopmental and dopamine hypotheses are leading theories of the pathoetiology of schizophrenia, but they were developed in isolation. However, since they were originally proposed, there have been considerable advances in our understanding of the normal neurodevelopmental refinement of synapses and cortical excitation-inhibition (E/I) balance, as well as preclinical findings on the interrelationship between cortical and subcortical systems and new in vivo imaging and induced pluripotent stem cell evidence for lower synaptic density markers in patients with schizophrenia. Genetic advances show that schizophrenia is associated with variants linked to genes affecting GABA (gamma-aminobutyric acid) and glutamatergic signaling as well as neurodevelopmental processes. Moreover, in vivo studies on the effects of stress, particularly during later development, show that it leads to synaptic elimination. We review these lines of evidence as well as in vivo evidence for altered cortical E/I balance and dopaminergic dysfunction in schizophrenia. We discuss mechanisms through which frontal cortex circuitry may regulate striatal dopamine and consider how frontal E/I imbalance may cause dopaminergic dysregulation to result in psychotic symptoms. This integrated neurodevelopmental and dopamine hypothesis suggests that overpruning of synapses, potentially including glutamatergic inputs onto frontal cortical interneurons, disrupts the E/I balance and thus underlies cognitive and negative symptoms. It could also lead to disinhibition of excitatory projections from the frontal cortex and possibly other regions that regulate mesostriatal dopamine neurons, resulting in dopamine dysregulation and psychotic symptoms. Together, this explains a number of aspects of the epidemiology and clinical presentation of schizophrenia and identifies new targets for treatment and prevention.

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