Synaptic function programs in neuron-astrocyte CO-cultures from human post-mortem brain tissue - compelling evidence establishes synaptic pathology as a central convergence point for a growing…

The National Institute of Mental Health awarded The McLean Hospital Corporation $463,229 on September 1, 2026, under the Mental Health Research Grants program (CFDA 93.242) to investigate synaptic function programs in neuron-astrocyte co-cultures derived from human post-mortem brain tissue.

The award funds research combining primary human astrocyte cultures and induced pluripotent stem cell-derived astrocytes and neurons isolated from the same human post-mortem brain donor tissue. The research examines coordinated gene expression programs—termed synaptic neuron astrocyte programs (SNAP)—that support synaptic functions through multicellular interactions between neurons and glial cells. The work addresses synaptic pathology as a convergence point across psychiatric, neurodevelopmental, and neurodegenerative disorders, with SNAP enriched in schizophrenia risk variants and reduced in schizophrenia and aging. Primary astrocytes are isolated from the frontal lobe, while dura mater-derived fibroblasts from the same donor are reprogrammed into induced pluripotent stem cells and differentiated into astrocytes and neurons to enable study of cell interactions within the same individual.

The period of performance runs from September 1, 2026, through August 31, 2028. Work is performed in Belmont, Massachusetts. This is a Project Grant, a non-renewable assistance type under the Mental Health Research Grants program.

Synaptic function programs in neuron-astrocyte CO-cultures from human post-mortem brain tissue - compelling evidence establishes synaptic pathology as a central convergence point for a growing number of psychiatric, neurodevelopmental and neurodegenerative brain disorders. While there is broad agreement that synaptic functions require cooperation between neurons and astrocytes, investigations on synaptic pathology have largely focused on distinct cellular components. We showed multicellular, concerted gene expression programs supporting synaptic functions in neurons and astrocytes. We call these coordinated gene expression programs 'synaptic neuron astrocyte program' (snap). Snap is enriched in risk variants for schizophrenia and is reduced in this disorder and in aging. Snap points to the importance of investigating synaptic dysfunction in the context of multicellular interactions between neurons and glial cells. Given the complexity and heterogeneity of brain disorders, human-derived models of the brain such as induced pluripotent stem cells (ipscs), that can be manipulated in experiments, are uniquely informative to understand brain disease biology. However, the extent to which cells in culture recapitulate human brain biology remains unresolved. At least in part, this is due to challenges in studying cell interactions under different experimental paradigms yet in the same persons. Here, we combine state-of-the-art approaches developed by our groups to generate primary human astrocyte cultures as well as human ipsc-derived astrocytes and neurons from the same human postmortem brain tissue. Primary astrocytes are isolated from the frontal lobe, dura mater-derived fibroblasts from the same donor are reprogrammed into ipscs (DM-ipscs) and differentiated into astrocytes and neurons our long-term goal is to illuminate the role of multicellular programs involved in human brain biology and disease, including synaptic functions in the health brain and disease. Our hypothesis is that gene expression programs supporting synaptic functions are dynamically orchestrated across neurons and astrocytes. Built in these experiments is a rigorous validation of human-derived neuron-astrocyte CO-cultures as a tool for investigations on cell-to-cell synaptic mechanisms and synaptopathology in brain disorders. In aim 1 we will use single nucleus RNA sequencing to compare mono-cultures of human primary astrocytes and DM-ipsc-derived astrocytes and neurons to their cell counterparts in cortical tissue from the same donors. In aim 2, similar assays will be carried out on CO-cultures of human astrocytes (primary and DM-ipscs) and DM-ipsc-neurons from the same donors. These studies will offer the first evidence for the feasibility and relevance of human-derived primary and ipsc- derived multicellular models of synaptic functions. Their rigor will be supported by direct comparison of gene expression programs and canonical protein expression from the same donors and specific brain regions of origin. Their broad impact and applicability reside in the convergence of synaptopathies in a growing number of brain disorders and in their potential to further validate and enhance the use of ipscs from live donors.