The Science Behind the Psychiatric Biomarkers Network Study
The Psychiatric Biomarkers Network aims to identify biomarkers by testing hypotheses emerging from genetic studies of schizophrenia and bipolar spectrum disorders and related illnesses.
The emerging neurobiology of psychiatric disorders
In recent years, large-scale genetics studies have identified many hundreds of genetic variants (typically small differences in DNA sequences) that increase individuals’ risk for schizophrenia, bipolar disorder, and other mental health conditions. Progress is being made in mapping a growing number of these variants to specific genes and proteins, providing neuroscientists with clues about what aspects of brain development and function contribute to these conditions. An emerging theme from this research is the importance of synapses – the specialized connections through which neurons, the key brain cells involved in information processing, communicate with each other. Findings from genetics and neurobiology are now pinpointing proteins within these synapses that contribute to disease processes or are affected by them. Synapse health is central to many neurological and psychiatric disorders, especially the range of conditions that result in cognitive impairments. Results from genetics and neurobiology have highlighted a central role for synaptic dysfunction and synapse loss in schizophrenia and bipolar disorder. Although these conditions are complex and influenced by diverse genetic and environmental risk factors, it is for this reason that the first major focus of the Psychiatric Biomarkers Network is discovering biomarkers that could indicate the number and condition of synapses.
One Specific Hypothesis:
During brain development in infancy and childhood, the billions of neurons in the human brain form hundreds of trillions of synapses. As a child develops, these synapses are “refined”: connections that are used are maintained and strengthened as children learn and grow, while those that are not used are weakened and eventually eliminated by the brain's resident immune cells (called microglia), in a process called “pruning”. Such synaptic refinement eventually results in adult patterns of cognition and behavior, importantly including greater cognitive control of thought, emotion, and behavior.
During adolescence, the rate of synapse elimination (pruning) in the prefrontal and temporal regions of the cerebral cortex– regions involved in higher cognition and executive function - is greater than the rate of synapse generation, which in typical development results in a thinning of specific brain regions (cortical gray matter) that can be observed by neuroimaging. Among individuals who develop schizophrenia, the thinning of cortical gray matter is excessive. These results are one piece of evidence for the theory that too much synapse pruning during adolescent brain development increases the risk for schizophrenia. Recent genetic findings suggest a cellular mechanism that could explain this excessive synaptic pruning during adolescence (Feinberg 1982; Johnson and Stevens 2018).
The complement system is part of the body’s immune system that instructs the removal of abnormal or invading materials. It performs similar functions in the brain in response to infection or damage. It also plays a critical role in healthy brain development by contributing to the elimination of unused synapses. The complement protein C4A is recruited to mark weak synapses that should be pruned. The C4A tagged synapses recruit other proteins, generating an “eat me” signal that is detected by the microglia, which then engulf and remove the tagged synapses. Both, genetic variation that is thought to reduce expression of genes which produce synaptic components, as well as genetic variation that increases the amount of C4A made in the brain increase risk for schizophrenia. In addition, higher levels of C4A protein have been found to be higher on average – variation is expected in any complex and heterogeneous condition - in individuals with schizophrenia compared to those without. Based on the adolescent onset of schizophrenia and other scientific data, one current hypothesis is that schizophrenia may result from excessive pruning of synapses, driven in part, in many affected individuals by excessive C4A protein levels (Sekar et al., 2016). One specific goal of the PBN is to measure C4A and other complement proteins in the cerebrospinal fluid (CSF) and blood of individuals with psychosis, in hopes of identifying which patients could potentially benefit from future therapeutics that might target the complement system or microglia.