Release of neurotransmitters from a presynaptic nerve terminal initiates synaptic transmission, a key form of information transfer between neurons. The presynaptic active zone, a dense protein network that serves as the site of synaptic vesicle fusion, is a unique feature of the presynaptic nerve terminal compared to other secretory pathways. The active zone orchestrates the synaptic vesicle cycle and endows synaptic transmission with incredible speed and precision required for the complex functions the brain fulfills. ELKS is a protein that localizes tightly to the active zone. Published data and our preliminary results suggest that it fulfills several roles in neurotransmitter release. Human genetic studies found ELKS1 to be associated with neurodevelopmental disorders of speech, indicating relevant functions of ELKS in humans. However, the exact functions of mammalian ELKS are unknown and its mechanisms are not understood. The goal of this study is to understand how ELKS, encoded by two genes in vertebrates, functions at the active zone to contribute to its roles in release. We have previously found that deletion of the ELKS2 gene in mice increases the pool of readily releasable synaptic vesicles at inhibitory synapses. In contrast, my preliminary data indicate that ELKS1 may serve opposing roles in inhibitory transmission. These data lead to the hypothesis that ELKS isoforms differentially tune the parameters of neurotransmitter release. To address this hypothesis, I am using a combination of whole-cell patch clamp recordings, molecular biology, and mouse genetic tools. In the first aim, I will determine the mechanisms by which ELKS2 suppresses release. I will pursue rescue experiments in an ELKS2 knock-out to determine which sequences are necessary and sufficient to suppress release.
In aim 2, I will ask the question whether ELKS1 fulfills roles similar to ELKS2. Our preliminary data suggest that there may be some divergent roles between ELKS1 and ELKS2, and I will address these roles in newly generated ELKS1 knock-out mice.
My third aim rests on the hypothesis that intricate interplay between ELKS1 and ELKS2 fine-tunes release. I will test two specific working models that could account for our preliminary data, and I will consider alternative outcomes. In summary, my work will provide novel insight into how the makeup of active zones controls synaptic transmission, and, ultimately, how molecular deficiencies at the active zone may contribute to neurological disease.

Public Health Relevance

Studying the molecular mechanisms that underlie synaptic transmission is crucial for a better understanding of brain function and neurological disease. Human genetic studies have identified that mutations in the components of the presynaptic active zone, a highly specialized molecular machine that organizes the release of neurotransmitters, are associated with cognitive disorders and autism. My work aims to define how the active zone functions to fine-tune neuronal communication.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Stewart, Randall R
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Harvard Medical School
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Wang, Shan Shan H; Held, Richard G; Wong, Man Yan et al. (2016) Fusion Competent Synaptic Vesicles Persist upon Active Zone Disruption and Loss of Vesicle Docking. Neuron 91:777-791
Held, Richard G; Liu, Changliang; Kaeser, Pascal S (2016) ELKS controls the pool of readily releasable vesicles at excitatory synapses through its N-terminal coiled-coil domains. Elife 5:
Liu, Changliang; Bickford, Lydia S; Held, Richard G et al. (2014) The active zone protein family ELKS supports Ca2+ influx at nerve terminals of inhibitory hippocampal neurons. J Neurosci 34:12289-303