The role of endozepine diazepam binding inhibitor on the structural plasticity of dendrite spines in neurodegenerative diseases

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In the central nervous system (CNS), the structural plasticity of dendritic spines, reflecting the establishment or destruction of synapses, is highly dynamic. Emerging evidence suggests that such structural alterations in synaptic connectivity, are likely the underpinning of cognitive processes in response to not only physiological stimuli but also many, if not all, neurodegenerative diseases, such as Alzheimer's disease (AD) and synucleinopathies. So far, though a few intrinsic and extrinsic modulators of the structural plasticity of dendrite spines have been identified, more are kept being discovered. Recently, we observed elevation of TSPO either upon benzodiazepine administration in WT mice or in plaque-associated microglia in the AD mouse model, leading to a global or regional decrease of dendritic spine plasticity, respectively. Such evidence prompted our interest in endogenous TSPO ligands designated by the generic term ‘endozepines’ that may regulate the dendritic spine dynamics across healthy condition and neurodegenerative diseases. One of the best-known endozepines is the diazepam binding inhibitor (DBI), a 9 kDa peptide primarily produced and released by astrocytes in the CNS, and prominently bind to TSPO with high affinity. In our preliminary work, we have observed increased dendritic spine density in WT mice upon DBI knockdown using viral vectors with shRNA driven by a U6 (cell-type unspecific) promoter, hinting DBI's role in regulating dendritic spines. On top of that, we observed a significant increase of DBI from plaque-associated astrocytes in an AD mouse model. Hence, based on these data, it is tempting to hypothesize that astrocytes and microglia intertwine in the neurodegenerative brain via the DBI-TSPO signaling pathway, which might collaboratively affect dendritic spines. In this project, we plan to (WP1) characterise the role of astrocytic DBI in regulating the structural plasticity of dendritic spines, as well as on microglial morphology and functions. After that, we will explore (WP2) whether and how the dendritic spines and microglia are to be affected in the neurodegenerative diseases upon astrocytic DBI depletion. To extend our study in a translational manner, we will then validate (WP3) our findings in post-mortem human tissues, investigating alterations of astrocytic DBI signalling and subsequent microglial synaptic engulfment in patients with neurodegenerative diseases in comparison to healthy controls. In summary, we expect these experiments will decipher the role of astrocytic DBI as a physiological modulator of dendritic spines, and may as a common therapeutic target for restoring synaptic pathology in a variety of neurodegenerative diseases.