Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms

Mancini, Valentina; Saleh, Muhammad G.; Delavari, Farnaz; Bagautdinova, Joëlle; Eliez, Stéphan

doi:10.1016/j.biopsych.2023.03.021

Cited by 11 publications

(3 citation statements)

References 87 publications

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“…Could impaired behavioural phenotype in Tbx1 +/- mice be due to the increased levels of glutamate and glutamine reported here? A recent study reported that 22q11DS patients with psychotic symptoms had increased levels of glutamate and glutamine in the hippocampus and in the superior temporal cortex (Mancini et al, 2023). Previously, increased glutamate and myo-inositol were found in the hippocampus of 22q11DS patients with schizophrenia (da Silva Alves et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

Caterino,

Paris,

Torromino

et al. 2024

Preprint

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Introduction The brain-related phenotypes observed in 22q11.2 deletion syndrome (22q11.2DS) are highly variable and their origin is poorly understood. Changes in brain metabolism may cause or contribute to the phenotypes, given that many of the deleted genes (approx. 10%) are implicated in metabolic processes, but this is currently unknown. It is clearly important to address this knowledge gap, but in humans, the primary material required for studying brain metabolism is inaccessible. For this reason, we sought to address the issue using two mouse models of 22q11.2DS. Methods We used three independent approaches to investigate brain metabolism in young adult mice, namely, mass spectrometry, nuclear magnetic resonance spectroscopy and transcriptomics. We selected to study primarily Tbx1 single gene mutants because it is the primary candidate disease gene. We then confirmed key findings in the multi-gene deletion mutant Df1/+. Results We found that Tbx1 mutants have alterations of specific brain metabolites, including methylmalonic acid, which is highly brain-toxic, as well as a more general metabolomic imbalance. We provide transcriptomic evidence of an interaction genotype-vB12 treatment, and behavioural evidence of a response to vB12 treatment, which rescued some of the behavioural anomaly observed in Tbx1 mutants. We conclude that Tbx1 haploinsufficiency causes extensive brain metabolic anomalies, which are partially responsive to vB12 treatment. We suggest that alterations of glutamine-glutamate metabolism and fatty acid metabolism are key components of the metabolic phenotype in these mutants.

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Section: Discussionmentioning

confidence: 99%

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

Caterino,

Paris,

Torromino

et al. 2024

Preprint

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“…Notably, ulotaront was reported to improve prepulse inhibition deficits induced by the glutamate NMDA receptor antagonist MK-801 in wild-type, but not TAAR1 knockout mice, suggesting that reversal of the effects are TAAR1-dependent [ 29 ]. Our data now indicate that ulotaront modulates excitatory glutamatergic synaptic transmission as well as intrinsic neuronal excitability in the hippocampus (where the principal neurons are glutamatergic cells), which is believed to play a central role in the pathophysiology for schizophrenia [ 42 , 43 ]. These alterations in hippocampal activity might lead to downstream effects on dopamine neuron activity in the midbrain and striatum, complementing and/or supporting the previously reported capacity of ulotaront to decrease VTA neuronal firing and normalize elevated striatal dopamine synthesis capacity [ 28 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

TAAR1 agonist ulotaront modulates striatal and hippocampal glutamate function in a state-dependent manner

Yang,

Ghoshal,

Hubbard

et al. 2023

Neuropsychopharmacol.

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Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated receptor 1 (TAAR1) agonism has emerged as a potential new treatment approach for schizophrenia. While current evidence implicates TAAR1-mediated regulation of dopaminergic tone as the primary circuit mechanism, little is known about the effects of TAAR1 agonists on the glutamatergic system and excitation-inhibition balance. Here we assessed the impact of ulotaront (SEP-363856), a TAAR1 agonist in Phase III clinical development for schizophrenia, on glutamate function in the mouse striatum and hippocampus. Ulotaront reduced spontaneous glutamatergic synaptic transmission and neuronal firing in striatal and hippocampal brain slices, respectively. Interestingly, ulotaront potentiated electrically-evoked excitatory synaptic transmission in both brain regions, suggesting the ability to modulate glutamatergic signaling in a state-dependent manner. Similar striatal effects were also observed with the TAAR1 agonist, RO5166017. Furthermore, we show that ulotaront regulates excitation-inhibition balance in the striatum by specifically modulating glutamatergic, but not GABAergic, spontaneous synaptic events. These findings expand the mechanistic circuit hypothesis of ulotaront and TAAR1 agonists, which may be uniquely positioned to normalize both the excessive dopaminergic tone and regulate abnormal glutamatergic function associated with schizophrenia.

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“…Longitudinally, there were steeper thalamic volume decreases over time in individuals with 22qDel who experienced auditory hallucinations. In 22qDel, lower hippocampal tail volume has been related to verbal learning impairments [27], and hippocampal volume loss over time in 22qDel has been linked to altered local balance of excitatory and inhibitory neurotransmitter metabolites [28].…”

Section: Introductionmentioning

confidence: 99%

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

Schleifer,

O’Hora,

Fung

et al. 2023

Preprint

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The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in 22qDel (n=96, 53.1% female), 22qDup (n=37, 45.9% female), and TD controls (n=80, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the effect of 22q11.2 gene dosage was examined using linear mixed models. Age-related changes were characterized with general additive mixed models (GAMMs). Positive gene dosage effects (22qDel < TD < 22qDup) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age- related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

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Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms

Cited by 11 publications

References 87 publications

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

TAAR1 agonist ulotaront modulates striatal and hippocampal glutamate function in a state-dependent manner

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

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