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Study Links Genetic Mutation to Schizophrenia Behaviors

Researchers from the University of Illinois Urbana-Champaign, in collaboration with teams in Massachusetts and Germany, have identified a genetic mutation associated with schizophrenia in two human patients. This mutation not only affects human subjects but also induces schizophrenia-like behaviors in genetically modified mice, representing a significant discovery of a direct genetic connection to psychotic disorders.

The mutation results in heightened levels of glycine decarboxylase (GLDC), an enzyme pivotal for glycine regulation in the brain. Glycine is essential as it activates NMDA receptors linked to the neurotransmitter glutamate, which plays a crucial role in synaptic transmission and plasticity.

As the study’s lead, Uwe Rudolph, a professor of comparative biosciences at Illinois, noted, “The genetics underlying schizophrenia is immensely complex, and it is not common for specific mutations in patients to be directly associated with the condition. Currently, schizophrenia is diagnosed based solely on clinical assessments rather than through laboratory tests or imaging methodologies.” He expressed hope that insights from these rare mutations could illuminate vital biochemical and physiological processes relevant to schizophrenia.

The investigation was initiated after the discovery of the genetic mutation in two schizophrenia patients at McLean Hospital in Belmont, Massachusetts. These patients exhibited multiple copies of a DNA segment that included the GLDC gene. Intrigued by the potential role of this mutation in their symptoms, the research team at McLean collaborated with Rudolph’s lab to create mouse models carrying the same mutation.

The resulting mice displayed behaviors characteristic of schizophrenia. To further clarify the genetic relationship, researchers also developed mouse lines with multiple copies of selected genes from the larger chromosomal segment linked to the patients’ conditions, ultimately isolating the GLDC gene.

“Our findings indicated that merely having extra copies of the GLDC gene led to the schizophrenia-like behaviors we documented,” Rudolph stated. He is additionally a member of the Neuroscience Program and the Carl R. Woese Institute for Genomic Biology at Illinois.

To decipher why the surplus of the GLDC gene led to these behavioral changes, the team focused on the biochemical activity in the mice’s brains, examining glycine levels and the functionality of NMDA receptors.

“We posited that excessive GLDC could decrease glycine levels, as it is responsible for glycine breakdown. This would lead to insufficient glycine to activate NMDA receptors,” explained Maltesh Kambali, an Illinois postdoctoral researcher and the paper’s lead author. “Our measurements indicated elevated GLDC enzyme activity in the brains of the modified mice, supporting this hypothesis.”

However, glycine levels did not show a significant difference between the mice with extra GLDC and healthy controls. Consequently, the research team enlisted the help of experts in Germany, who employed advanced techniques to monitor glycine distribution within the brain.

Investigations revealed that despite comparable total glycine levels, there was notably lower glycine availability in the synaptic regions of the hippocampus in mice with GLDC duplication, reducing the substance’s efficiency in activating NMDA receptors.

To explore the reasons for the observed deficits in this specific brain area, the Illinois group partnered with Harvard Medical School researchers to conduct functional studies on the impacted hippocampal subregion, identified as the dentate gyrus. They found reduced activity at neural synapses, which are critical junctions for neuronal signaling. Significant differences in long-term potentiation, which enhances synaptic strength during learning, were also noted.

Kambali remarked, “The correspondence between our glycine measurements and long-term potentiation indicators in the dentate gyrus region, absent in other hippocampal areas, is particularly noteworthy. This aligns with theories suggesting a connection between psychosis development and dentate gyrus activity.”

A biochemical assessment revealed lower activity in several pathways previously linked to schizophrenia within the dentate gyrus of the mice with increased GLDC. This suggests that the elevated GLDC and concurrent decrease in glycine functionally impair NMDA receptors, contributing to the psychotic symptoms observed.

The comprehensive study has been documented in the journal Molecular Psychiatry.

Rudolph concluded, “This research effectively illustrates how GLDC acts as a novel regulator for NMDA receptors. These receptors play a significant role in the pathophysiology of schizophrenia. Notably, their dysfunction is crucial regardless of the disease context, as NMDA receptors are vital for various brain functions, including learning and memory.”

This research received funding from multiple institutions, including the National Institutes of Health, the Shervert Frazier Research Institute at McLean Hospital, and the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, along with support from a Harvard Brain Science Initiative Bipolar Disorder Seed Grant.

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