Identification of a non-invasive neuroimaging biomarker of prenatal synaptic development

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Project summary and abstract One of the most profound changes that occurs during gestational development is the rapid increase in the connections between neurons. Synaptogenesis, or the formation of synapses, that occurs in utero is critical for subsequent neural development, and several mental and developmental disorders are believed to be the resultant of alterations in prenatal synaptogenesis. Synaptic quantification, until recently, has required post- mortem tissue, so direct evidence linking prenatal synaptic disruptions with postnatal neural and behavioral development has been limited. We have recently developed a novel positron emission tomography (PET) radioligand ([11C]UCB-J) that targets synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in almost all synaptic vesicles, and have demonstrated that [11C]UCB-J is able to detect subtle alterations in human disorders, such as Alzheimer’s disease. We have conducted a pilot study using [11C]UCB-J to quantify synaptic development throughout prenatal and postnatal development in non-human primates and have found striking changes in [11C]UCB-J binding that parallel post-mortem measures of synaptogenesis. Therefore, longitudinally characterization of synaptic density with [11C]UCB-J has the potential to provide unprecedented insight into the developmental mechanisms that underlie mental illness. This proposal will use [11C]UCB-J to quantify synapses throughout gestation and the first nine postnatal months in non-human primates to determine the predictive relationship between prenatal synaptic development and postnatal development of the brain and cognition. In the first aim, we will quantify SV2A during gestation (post-conception days 120 and 150) and following birth (postnatal days 15, 30, 60, 120 and 240) to determine if development trajectories of SV2A co-vary with changes in reward learning, working memory and response inhibition, which are cognitive domains known to be altered in mental illness. The second aim will determine the relationship between prenatal SV2A density and magnetic resonance (MR) measures in order to identify a putative MR biomarker of prenatal synaptic density that could serve as a noninvasive diagnostic tool for use in human infants. Measures of brain morphometry, myelination and functional connectivity will be longitudinally assessed in the same infant non-human primates used in Aim 1 following birth (postnatal days 30, 60, 120 and 240) and related to synaptic and cognitive development trajectories of the same monkey. These studies of normal development in non- human primates will provide the preliminary data for future studies examining SV2A in animal models of mental illness, and ultimately lead to the identification of noninvasive MR imaging biomarker of prenatal synaptic density that can be safely acquired in human infants and children and serve as a diagnostic tool.