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Schizophrenia affects tens of millions of people worldwide and requires lifelong treatment and medical support. To develop more effective therapies, researchers must understand how the disease alters brain networks. A team led by Zoltán Nusser at the HUN-REN Institute of Experimental Medicine (HUN-REN IEM) has achieved a major breakthrough by creating a high-resolution method to study synaptic proteins at individual synapses in human brain tissue, announced the Hungarian research center.
The underlying processes of schizophrenia are known to involve the dorsolateral prefrontal cortex (DLPC), that plays a key role in the development of cognitive impairments. Previous genetic studies suggest that disturbances may occur in the functioning of excitatory, so-called glutamatergic synapses in this region. However, examining genes alone is not enough to accurately map the problem: changes at the protein level must also be observed, as gene expression does not provide information about the quantity and distribution of proteins in individual synapses.
The HUN-REN research team led by Zoltán Nusser has made a breakthrough in this area. While high-resolution microscopic data examining the distribution of synaptic proteins has so far come almost exclusively from rodents, the research group developed a method that allows the molecular composition of synapses in postmortem human brain tissue to be examined with high sensitivity and accuracy. The samples for the studies were provided by the HUN-REN IEM Human Brain Research Laboratory.
“Our research group has successfully optimized a post-embedding immunofluorescence labeling procedure for human samples. From sections embedded in synthetic resin, a few hundred nanometers thick, we were able to obtain quantitative data on the amount and spatial distribution of synaptic proteins using confocal and STED super-resolution microscopy, with a resolution of up to 40 nanometers,” said Andrea Lőrincz, the first author of the article, about the research.
The uniqueness and great advantage of this method is that dozens of different proteins can be labeled in the same synapse, now even in human tissue.
One of the most interesting findings of the study was that the overall structure of excitatory synapses remained surprisingly stable in the cerebral cortex of patients with schizophrenia. The density and size of the synapses, as well as the amount of the main glutamate receptors and presynaptic proteins, did not differ from those in healthy samples.
The researchers focused on a type of brain cell called parvalbumin-positive (PV+) interneurons, that are known to be involved in schizophrenia. They found that these cells had about 30% less parvalbumin protein in brains of people with schizophrenia compared to healthy brains. In addition, certain receptors that help these cells receive signals, called NMDA receptors, were reduced, while other receptors, called AMPA receptors, stayed the same.
According to Andrea Lőrincz, the results suggest that excitatory synapses in the prefrontal cortex are not generally impaired in schizophrenia, but that molecular changes occur selectively in the synapses of certain cell types. ”Due to the reduced NMDA receptor levels observed in PV+ cells, these cells may be less able to respond appropriately to excitatory signals, which in the long term may disrupt the delicate balance between the excitatory and inhibitory systems of the brain and contribute to the cognitive decline characteristic of the disease,” explained the researcher.
The researchers say
the new method has significant potential not only for mapping the molecular background of schizophrenia, but also for other psychiatric and neurological diseases.
“We are confident that our technique will help us better understand which molecules play a key role in the development and progression of these diseases,” added Andrea Lőrincz.
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p style=”text-align: justify”>Via hun-ren.hu, Featured image: Pexels
The post Breakthrough Approach Brings Scientists Closer to Understanding Schizophrenia appeared first on Hungary Today.
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