Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Overview: Synapses are specialized structures for neurons to communicate with each other in the brain and individually tuned to distinct functional states to convey, filter and encode information in the neural network. Even among a genetically homogeneous population of neurons, heterogeneity in the probability of neurotransmitter release ( Pr ) at central synapses is widely observed but little is known about their key underpinnings. Despite significant efforts over the past several decades, technical difficulties to directly access the tiny structure of classical presynaptic boutons, not to mention the nanometer and sub- millisecond scale within which calcium ions drive neurotransmitter release, have precluded major breakthrough in solving this fundamental question.

Preliminary Data & Hypothesis: Our previous work showed that the morphological complexity of nerve terminals (characterize by main stalks with various number of swellings on each stalk) strongly correlates and predicts functional phenotypes among the same population of large auditory synapses (i.e. the calyx of Held)(Grande & Wang, J Neurosci 2011). We have obtained preliminary data to hypothesize that this diversity arises from different ratios of two distinct presynaptic morphological release modules in the same nerve terminal, namely Tight- and Loose-Nanodomain Modules, respectively (TNM & LNM). TNM contains few calcium channels but tightly coupled to synaptic vesicles (SVs) to give high Pr from stalks, whereas LNM has many loosely coupled calcium channels to produce low Pr from swellings. Combining simultaneously paired patch-clamp recordings from pre- and postsynaptic elements, advanced 2-photon and super-resolution fluorescence microscopy, molecular biology and computer modeling, we propose to address this hypothesis with the following Specific Aims :

1: To delineate the biophysical basis underlying synaptic heterogeneity;
2: To determine the key molecular substrates underlying TMN and LMN;
3: To define the impact of TMN and LNM on the encoding capacity of synapses by manipulating their relative weight in the same nerve terminal;

Significance: Synaptic heterogeneity expands the dynamic range of neurotransmission and plasticity, which is of paramount importance for representations and computations of rich sensory stimuli within a homogeneous population of neurons. Using the auditory brainstem as a model in which timing and intensity of inputs are critical cues for sound localization, this study will provide the first nanoscale insights into how the same synapses can diversify Pr and the magnitude and polarity of short-term plasticity for encoding a broad spectrum of information by varying presynaptic ensembles of distinct release modules with different subsynaptic coupling distance and density of calcium channels at the release sites.