The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia

Uliana, Daniela L.; Lisboa, Joao Roberto F.; Gomes, Felipe V.; Grace, Anthony A.

doi:10.1016/j.bcp.2024.116298

Cited by 7 publications

(3 citation statements)

References 253 publications

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“…administration did not produce any NMDARs hypofunctioning effect. In addition, one of the most accepted hypotheses is the E/I altered balance in SCZ and other diseases affecting cognitive abilities [19,[47][48][49]. In the "classical" condition, when modeling acute SCZ-like cognitive deficits, MK801 is systemically administered acutely, inducing the E/I altered ratio and the desynchronization of γ and θ bands oscillations [50][51][52].…”

Section: Discussionmentioning

confidence: 99%

PV+ optogenetic stimulations at specific frequencies in specific brain regions can restore navigational flexibility in an acute MK801 mouse model of schizophrenia

Patrono,

Černotová,

Svoboda

et al. 2024

Preprint

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Impairments of decision-making and behavioral flexibility in schizophrenia (SCZ) are currently the most investigated features. One convincing hypothesis explaining this cognitive impairment is the excitatory/inhibitory (E/I) ratio imbalance in brain regions such as the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC). An increased GLUergic excitatory activity and a decreased GABAergic inhibitory activity induces an mPFC-vHPC γ/θ band desynchronization in many tasks testing behavioral flexibility. However, these tasks were carried out using “perceptual” decision-making/flexibility but not navigational decision-making/flexibility. Our study addressed the role of frequency-specific optogenetic stimulations of GABAergic parvalbumin-positive (PV+) interneurons in mPFC (50Hz, γ-like) and vHPC (10Hz, θ-like) in an acute-MK801 mouse model of navigational inflexibility. We used the active place avoidance task on a rotating arena. Results showed that frequency-specific optogenetic stimulations of mPFC or vHPC acted differently in restoring navigational flexibility, advancing our knowledge of the pivotal role of PV+ activity in SCZ-like navigational decision-making/flexibility.

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Section: Discussionmentioning

confidence: 99%

PV+ optogenetic stimulations at specific frequencies in specific brain regions can restore navigational flexibility in an acute MK801 mouse model of schizophrenia

Patrono,

Černotová,

Svoboda

et al. 2024

Preprint

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“…Early clinical trials employing d -serine as a supplementary treatment to antipsychotics showed significant improvements in positive, negative, and cognitive symptoms in schizophrenic patients. Although larger-scale studies have obtained conflicting results, more phase II and III trials are ongoing [ 132 ]. Moreover, both preclinical and clinical studies have considered the co-administration of d -serine analogs together with d -amino acid oxidase inhibitors, such as Luvadaxistat and sodium benzoate, as therapeutic approaches to enhance NMDA receptor function in schizophrenia [ 133 ].…”

Section: Glutamatergic Alterations In Schizophreniamentioning

confidence: 99%

“…Preclinical studies have already provided exciting results, and pomaglumetad has entered clinical phase development. Pomaglumetad has been considered both in monotherapy and in combination with other treatments, although inconsistent results were observed in both [ 132 ]. A recent exploratory analysis suggested that pomaglumetad might be more effective in the early stages of the disease [ 147 ].…”

Section: Glutamatergic Alterations In Schizophreniamentioning

confidence: 99%

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

Nicosia,

Giovenzana,

Misztak

et al. 2024

IJMS

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Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.

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An introduction to the special issue “Sam Enna legacy of excellence”

Piette,

LeCount

2024

Biochemical Pharmacology

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The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia

Cited by 7 publications

References 253 publications

PV+ optogenetic stimulations at specific frequencies in specific brain regions can restore navigational flexibility in an acute MK801 mouse model of schizophrenia

PV+ optogenetic stimulations at specific frequencies in specific brain regions can restore navigational flexibility in an acute MK801 mouse model of schizophrenia

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

An introduction to the special issue “Sam Enna legacy of excellence”

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