New insights into the mechanisms underlying hippocampal atrophy in people at risk for psychosis

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 show that the temporo-limbic regions, and in particular the hippocampus, undergo a progressive shift in the ratio between the concentration of excitatory and inhibitory neurotransmitters. Additionally, we found that people with higher levels of excitatory neurotransmitters also had greater hippocampal volume loss 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 individuals at risk for psychosis and links these neural abnormalities to the emergence of psychotic symptoms.

Valentina Mancini, PhD, Faculty of Medicine, University of Geneva

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 impairment and functional impairment.”

The work may have clinical implications, Dr. Mancini added. “Current findings may inform new treatment strategies targeting early glutamatergic dysfunction in individuals at risk for psychosis. Given the essential role of the hippocampus in memory processes, prevention of excitatory-inhibitory imbalance and loss of volume could potentially attenuate the cognitive decline typically seen in psychotic patients.”