Glutamate imbalance impairs the hippocampus, leading to psychosis

Summary: People with a genetic risk for psychosis have an imbalance of the neurotransmitters glutamate and GABA in their brains, particularly in the hippocampus, a new study has found. This imbalance is associated with hippocampal atrophy, which can lead to the development of psychotic symptoms.

The findings could lead to new treatments for psychosis by targeting the glutamate-GABA imbalance.

Highlights:

1. People at genetic risk for psychosis have an imbalance of the neurotransmitters glutamate and GABA in their brain.
2. This imbalance is associated with hippocampal atrophy, which can lead to the development of psychotic symptoms.
3. The findings could lead to new treatments for psychosis by targeting the glutamate-GABA imbalance.

Source: Elsevier

Dysregulation of the dopamine neurotransmitter system has long been associated with schizophrenia and other forms of psychosis, but recently researchers have begun to examine the glutamate and GABA systems as well.

Studies have shown that an excitatory-inhibitory imbalance begins with improper functioning of NMDA-like glutamate receptors (NMDARs) in the temporal regions of the brain, but most of the evidence comes from studies of the brains of psychotic people, leaving question whether the imbalance results from or precedes psychotic symptoms.

Now, a new study in people with copy number 22q11.2 (22q11DS) variant deletion syndrome is probing the excitatory-inhibitory neurotransmitter system before the onset of psychosis.

Deletion carriers have a strong predisposition to psychiatric illnesses, including anxiety and mood disorders, and they have a 30% lifetime risk of developing psychotic disorders, including schizophrenia, at age adult.

These carriers present a unique opportunity for longitudinal studies of neuropsychiatric diseases because of the possibility of study and follow-up before and after the onset of these diseases.

The study appears in Biological psychiatryedited by Elsevier.

Researchers led by Valentina Mancini, PhD, at the Faculty of Medicine, University of Geneva, used magnetic resonance imaging (MRI) with proton magnetic resonance spectroscopy (MRS) to estimate levels of excitatory neurotransmitters glutamate and glutamine (Glx), and the neurotransmitter GABA inhibitors in the brains of 60 individuals with 22q11DS and 45 healthy controls.

They focused on three brain regions involved in the pathophysiology of schizophrenia: the anterior cingulate cortex (ACC), the superior temporal cortex (STC) and the hippocampus.

Deletion carriers had higher levels of Glx in hippocampus and STC, but not in ACC, compared to controls. Carriers also had significantly lower levels of GABA in the hippocampus, but not ACC or STC.

Importantly, among 22q11DS carriers, those with psychosis also had higher Glx levels in the hippocampus, suggesting that changes in the hippocampus may lead to downstream pathology.

Hippocampal atrophy has also been observed in the brains of people with schizophrenia. In the current study, Glx concentration was associated with greater atrophy, possibly indicating elevated hippocampal vulnerability.

“Our results highlight that the temporo-limbic regions, and in particular the hippocampus, undergo a gradual change in the ratio between the concentration of excitatory and inhibitory neurotransmitters,” said Dr. Mancini.

“Additionally, we found that people with higher levels of excitatory neurotransmitters also had greater loss of hippocampal volume over time. These people also began to experience psychotic symptoms, such as hallucinations and delusions. .

“Our study provides new insight into potential mechanisms underlying hippocampal atrophy in people at risk for psychosis and links these neural abnormalities to the emergence of psychotic symptoms.”

John Krystal, MD, editor of Biological psychiatry, said of the work: “This study of 22q.11 deletion syndrome, a syndrome at increased risk for schizophrenia, builds elegantly on previous findings linking excessive glutamate release to smaller cortical volumes, suggesting atrophy . This form of atrophy can contribute to cognitive and functional impairment.

The work may have clinical implications, Dr. Mancini added. “Current findings may inform new treatment strategies targeting early glutamatergic dysfunction in people at risk for psychosis.

Given the essential role of the hippocampus in memory processes, preventing excitatory-inhibitory imbalance and volume loss could potentially alleviate the cognitive decline typically seen in psychotic patients.

About this psychosis research news

Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Picture: Image is credited to Neuroscience News

Original research: Free access.
“An excitatory-inhibitory imbalance underlies hippocampal atrophy in people with 22q11.2 deletion syndrome with psychotic symptoms” by Valentina Mancini et al. Biological psychiatry

Abstract

An excitatory-inhibitory imbalance underlies hippocampal atrophy in people with 22q11.2 deletion syndrome with psychotic symptoms

Background

Abnormal levels of neurotransmitters have been reported in subjects at high risk for schizophrenia, leading to a change in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our goal was to explore live measures of excitatory/inhibitory balance in carriers of the 22q11.2 deletion, a population at genetic risk for psychosis.

Methods

Glx (glutamate + glutamine) and GABA + concentrations were estimated in the anterior cingulate cortex (ACC), superior temporal cortex (STC) and hippocampus using a MEGAPRESS sequence and the box. Gannet tools in 52 deletion carriers and 42 controls. T1-weighted images were acquired longitudinally and processed with Freesurfer v.6 to extract hippocampal volume. Subgroup analyzes were conducted in deletion carriers with psychotic symptoms.

Results

Although no difference was found in ACC, deletion carriers had higher levels of Glx in hippocampus and STC, and lower levels of GABA+ in hippocampus compared to controls. We further found a higher concentration of Glx in the hippocampus of psychotic deletion carriers. Finally, more pronounced hippocampal atrophy was significantly associated with increased levels of Glx in deletion carriers.

conclusion

We provide evidence for an excitatory/inhibitory imbalance in the temporal brain structures of deletion carriers, with a further increase in hippocampal Glx in individuals with psychotic symptoms associated with hippocampal atrophy. These findings are consistent with theories proposing abnormally high levels of glutamate as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.