Psychiatric Imaging Programme Transition

Synaptic terminals are the connections that allow information to flow from one nerve cell to the next. Synaptic terminal proteins, including one called SV2a, are key to this information flow & consequently for overall brain function. Loss of synaptic terminal proteins is thought to contribute to a number of illnesses, including schizophrenia. This highlights the importance of understanding potential mechanisms & effects of synaptic terminal protein loss. We focus on schizophrenia, although findings are likely to be relevant to other brain disorders, normal neurodevelopment & ageing as well.

Schizophrenia affects 1 in 100 people & is characterized by psychotic & negative symptoms, & cognitive impairments. It is a top ten cause of disability in working-age adults. A leading hypothesis proposes that synaptic terminal protein loss underlies impaired brain function to lead to the cognitive & other symptoms of schizophrenia. Complement proteins are produced by brain cells & regulate levels of synaptic terminals by tagging them to be broken down by immune cells called microglia. Some complement proteins are elevated in schizophrenia, & it is thought this leads to loss of SV2a, & other synaptic terminal proteins, in schizophrenia.

However, it remains unknown if the complement & SV2a changes underlie the symptoms & cognitive impairment in schizophrenia, or if further SV2a loss occurs during the course of the disorder. Moreover, it is not known if modulating SV2a impairs brain function in schizophrenia, as predicted. Finally, we lack approaches to measure synaptic terminal proteins at multiple time points, or to measure post-synaptic proteins.

We plan to address these critical gaps in understanding in three related work-packages. The first tests whether SV2A levels are altered at illness onset in schizophrenia relative to controls and if they reduce further during the course of schizophrenia using brain scans. It will also test if complement levels at presentation predict increasing cognitive impairment & other symptoms over time & if this is linked to altered SV2a levels.
The second tests if reducing SV2A activity impairs brain function & leads to symptoms in schizophrenia. This is important to understand the functional consequences of reductions in SV2A. We will use a drug called levetiracetam to reduce SV2A activity and compare its effects on brain function against a placebo using brain scans.

The third involves developing new approaches to image synaptic proteins. The current approach to image SV2A involves a small amount of radiation. This limits the number of scans someone can have, particularly in adolescence. It is necessary to scan adolescents & at multiple time-points to fully understand what happens to synaptic terminals during brain development & many brain disorders, which often begin in adolescence. To overcome this limitation, we aim to develop an ultra-low radiation approach & compare it to the current standard scan approach. This will involve scans in healthy volunteers.
In addition to synaptic terminal proteins, post-synaptic proteins are also important to brain function, and affected in schizophrenia & other brain disorders. However, there is currently no way of studying them in live humans, so it is not possible to test if post-synaptic proteins are involved in these disorders. To address this, we aim to develop a new PET tracer for post-synaptic markers. We will evaluate potential ligands & select the most promising ligand to take forward. If this experiment supports progression, we will then conduct a study to determine the reliability of the ligand in humans.

These studies have the potential to identify new approaches to treat schizophrenia, & other disorders with similar cognitive impairments & symptoms, including Alzheimer's disease, mood & autistic disorders. They also have the potential to develop new tools to further understanding of brain disorders.

Schizophrenia (SCZ) is a top ten cause of disability in young adults. Treatments are inadequate, particularly for the cognitive impairments, which increase early in SCZ. A leading hypothesis proposes that synaptic terminal loss is central to SCZ pathoetiology, leading to impaired neural function & symptoms, including cognitive impairments, & that the complement protein C4 plays a key role in this by tagging synaptic terminals for elimination.

Converging preclinical, genetic & post-mortem evidence supports it. PET imaging measures of a synaptic terminal marker, synaptic vesicle glycoprotein 2a (SV2a), mean the hypothesis can now be tested in vivo. PET studies in chronic SCZ show lower SV2a levels relative to controls. Preclinical studies show that lower SV2a levels lead to reduced neural activity & cognitive impairments, & we found that lower SV2a levels correlate with poorer cognitive performance & lower neural responses in SCZ.

The critical outstanding questions are thus:
1. Are SV2a levels lower at onset of SCZ & is there further loss?
2. Do C4 & SV2a levels predict increasing cognitive impairments & other symptoms in SCZ?
3. Does lowering SV2a activity impair neural function in SCZ?

Finally, synaptic loss may begin in adolescence during the prodromes to SCZ & other neurodevelopmental disorders, & also affect post-synaptic proteins. However, the field lacks the in vivo human approaches needed to test this.

We plan to address these issues in three related work-packages. The first two comprise imaging & experimental medicine studies in patients, whilst the third involves testing new human imaging approaches. These have the potential to identify novel treatment targets for SCZ, & biomarkers to assess them. They will also have benefits for understanding mechanisms in multiple other CNS disorders where synaptic protein loss, including of SV2a & post-synaptic proteins, is implicated (eg: autism, Alzheimer's disease & depression).