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Development of Tools to Explore the Synaptome

NAMHC Concept Clearance

Presenter

Michelle Freund, Ph.D.
Chief, Molecular Biotechnology and Neurotechnology Programs
Division of Neuroscience and Basic Behavioral Science (DNBBS)

Goal

The purpose of this initiative is to encourage applications to develop novel technologies and/or tools to facilitate the study of genes and proteins at the synapse on a large scale. Being able to characterize the synaptome at the level of hundreds to all genes/proteins would be a major advance for basic and translational research. The new tools should enable discovery science related to the synapse with substantially greater sensitivity, selectivity, and spatiotemporal resolution.

Rationale

Over the previous decade, technological developments in the life sciences have led to a proliferation of “-‘omics” approaches, whose goals involve comprehensive discovery of entire classes of biochemical or genetic entities for a given tissue or cell type. The nervous system represents a challenge and also an opportunity for this type of approach, because of its unique cellular and subcellular compartmentalization. A variety of methods are now available (or in development) for isolating components from different neural cell types and subcellular domains.

Much evidence points to specific pathologies related to the synapse in a number of brain disorders, including autism spectrum disorder, schizophrenia, and other neurodevelopmental and neurodegenerative disorders. The complexity and molecular diversity of the synapse are vast. A cell's identity can be characterized in a number of ways including its lineage, molecular composition, epigenetic state, activity profile, morphology, and the nature of its connections (inputs and outputs). Specifically, the ratio of excitatory vs. inhibitory inputs, the specific location of synapses, as well as the strength and capacity for plasticity can provide useful information about potential function. Furthermore, the dynamic nature of synapses must be considered when attempting to understand their role in circuit function.

The addition of new tools to further our understanding of synaptic function as it relates to plasticity, cell type specificity, neurodevelopment, and dysfunction of brain circuitry are critically needed. Tools to interrogate the synapse could include chip-based approaches to characterize gene or protein expression, protein capture, or novel technologies for biochemical or genetic analysis. These technologies should provide resources relevant to many of the existing Blueprint programs, especially neuroplasticity, cognition, disease research, and therapeutic target discovery.

Anticipated Outcomes:

  • Availability of novel tools and/or technology that will enable broader assessment of the synaptome.
  • Improvements of existing tools that substantially increase efficiency and accuracy, greatly improve detection and/or resolution, substantially reduce costs, or increase throughput.

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