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

Howes, Oliver; Shatalina, Ekaterina

doi:10.1016/j.biopsych.2022.06.017

Cited by 129 publications

(81 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More importantly, striatal dopamine release is mainly innervated via projections from the frontal cortex Kegeles et al, 2010). This ties to the previously described concept of an imbalance in excitation and inhibition within cortical networks, more specifically a lower inhibition in frontal networks leading to an amplified innervation of dopaminergic neurons in the striatum (Howes and Shatalina, 2022). Empirical evidence in support of this concept has been provided by administration of ketamine intervention in mice, leading to an increased synthesis of striatal dopamine -an effect that could be counteracted by activating inhibitory signals within cortical networks (Kokkinou et al, 2021).…”

Section: Considering This Established Contribution Of Dopamine the Qu...supporting

confidence: 66%

Circadian Rhythms in Auditory Hallucinations and Psychosis

Ngo¹,

Andreou²,

Obleser³

2022

Preprint

View full text Add to dashboard Cite

The near-24 hour patterns called circadian rhythms are imprinted in all organisms and influence virtually all aspects of human physiology and behaviour. This recognition of a functioning circadian clockwork permeating essentially all healthy functioning of body and mind quickly leads to the realisation that, in turn, human ailments should be probed for the degree to which they are rooted in or are at least marked by disruptions and dysregulations of circadian clock functions in the human body. In this review, we will focus on psychosis as a key mental illness and foremost one of its cardinal symptoms: auditory hallucinations. We will discuss recent empirical evidence and conceptual advances probing the potential role of circadian disruption in auditory hallucinations. Moreover, an imbalance in excitation and inhibition within cortical networks, which in turn drive a disinhibition of dopaminergic signalling will be highlighted as central physiological mechanism. Finally, we will be proposing two ways of experimentally intervening on the circadian disturbances that occur in psychotic hallucinators.

show abstract

Section: Considering This Established Contribution Of Dopamine the Qu...supporting

confidence: 66%

Circadian Rhythms in Auditory Hallucinations and Psychosis

Ngo¹,

Andreou²,

Obleser³

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Specifically, boys physiologically appear to require a lower maturational reduction in local functional connectivity in such areas during the transition from childhood to adulthood (Pujol et al, 2021). Therefore, it is possible that the risk of developing schizophrenia in this critical period and the higher incidence in males (Howes and Shatalina, 2022), could to some extent be related to the effect of environmental stressors on cortical inhibitory interneurons, presumably via promoting excessive synaptic pruning (Howes and Shatalina, 2022;Ouyang et al, 2017;Paus et al, 2008),…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the advances in dopamine and glutamate neurotransmission research in schizophrenia (Uno and Coyle, 2019;Howes and Shatalina, 2022), converging evidence has indicated that the gamma-aminobutyric acid (GABA) interneuron system may be defective at multiple levels of the neuroaxis. Neurophysiological studies have demonstrated GABA systemrelated deficiencies in the modulation of brainstem reflexes (Swerdlow et al, 2006;San-Martin et al, 2020), auditory stimuli filtering (Kim et al, 2020), inhibitory control of corticospinal pathway and prefrontal evoked responses (Kim et al, 2020;Li et al, 2021) and cortical synchronization (Uhlhaas and Singer, 2015;Ferrarelli and Phillips, 2021).…”

Section: Introductionmentioning

confidence: 99%

Mapping alterations in the local synchrony of the cerebral cortex in schizophrenia

Pujol

Mané

et al. 2022

Preprint

View full text Add to dashboard Cite

Observations from different fields of research coincide in indicating that a defective gamma-aminobutyric acid (GABA) interneuron system could be among the primary factors accounting for the varied clinical expression of schizophrenia. GABA interneuron deficiency is locally expressed in the form of neural activity desynchronization. We mapped the functional anatomy of local synchrony in the cerebral cortex in schizophrenia using a novel functional connectivity MRI approach. Patients with schizophrenia showed weaker local functional connectivity (i.e., lower MRI signal synchrony) in a set of cerebral cortex areas largely coinciding with the synchronization effect of the GABA agonist alprazolam and the cortical areas showing higher density of parvalbumin and somatostatin GABA interneurons in humans. Our results provide detail of the functional anatomy of synchrony changes in the cerebral cortex in schizophrenia and suggest which elements of the interneuron system are affected. The information could ultimately be relevant in the search for specific treatments.

show abstract

“…Recent advances in stem cell technology, now allowing to obtain iPSCs from blood, skin, or other somatic tissues and their reprogramming into cell types of the central nervous system, holds promise for the understanding of the developmental functional cellular mechanisms that connect genetic with an increased SZ risk at unprecedented resolution (Howes and Shatalina 2022). For example, several recent studies have shown the deleterious effect of deletions and aberrant expression of NRXN1 gene on neuronal excitability and synaptic function in iPSC-derived neurons (Flaherty et al 2019;Pak et al 2021;Avazzadeh et al 2021).…”

Section: Induced Pluripotent Stem Cell (Ipsc) Modellingmentioning

confidence: 99%

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

2022

View full text Add to dashboard Cite

Since more than 3 decades, schizophrenia (SZ) has been regarded as a neurodevelopmental disorder. The neurodevelopmental hypothesis proposes that SZ is associated with genetic and environmental risk factors, which influence connectivity in neuronal circuits during vulnerable developmental periods. We carried out a non-systematic review of genetic/environmental factors that increase SZ risk in light of its neurodevelopmental hypothesis. We also reviewed the potential impact of SZ-related environmental and genetic risk factors on grey and white matter pathology and brain function based on magnetic resonance imaging and post-mortem studies. Finally, we reviewed studies that have used patient-derived neuronal models to gain knowledge of the role of genetic and environmental factors in early developmental stages. Taken together, these studies indicate that a variety of environmental factors may interact with genetic risk factors during the pre- or postnatal period and/or during adolescence to induce symptoms of SZ in early adulthood. These risk factors induce disturbances of macro- and microconnectivity in brain regions involving the prefrontal, temporal and parietal cortices and the hippocampus. On the molecular and cellular level, a disturbed synaptic plasticity, loss of oligodendrocytes and impaired myelination have been shown in brain regions of SZ patients. These cellular/histological phenotypes are related to environmental risk factors such as obstetric complications, maternal infections and childhood trauma and genetic risk factors identified in recent genome-wide association studies. SZ-related genetic risk may contribute to active processes interfering with synaptic plasticity in the adult brain. Advances in stem cell technologies are providing promising mechanistic insights into how SZ risk factors impact the developing brain. Further research is needed to understand the timing of the different complex biological processes taking place as a result of the interplay between genetic and environmental factors.

show abstract

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

Cited by 129 publications

References 153 publications

Circadian Rhythms in Auditory Hallucinations and Psychosis

Circadian Rhythms in Auditory Hallucinations and Psychosis

Mapping alterations in the local synchrony of the cerebral cortex in schizophrenia

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

Contact Info

Product

Resources

About