Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease

Abstract

Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse.

Keywords: LTD; LTP; function; homeostatic; modulation; presynaptic; structure.

Figure 1

Presynaptic terminals are complex structures. (a) Transmission electron micrograph taken from rat hippocampal neuropil highlighting presynaptic terminals. The right panel is a close-up view of the yellow box in the left panel. Modified from Atlas of Ultrastructural Neurocytology on Synapse Web by Josef Spacek, Kristen Harris, and John Fiala. http://synapseweb.clm.utexas.edu/atlas. (b) Quantitative three-dimensional model of a section through an average presynaptic terminal displaying >300,000 proteins in atomic detail. The active zone is shaded red at bottom. From Wilhelm et al. (2014). (c) Three-dimensional model of a prototypical synaptic vesicle (close up) containing dozens of proteins in stoichiometrically accurate atomic detail. From Takamori et al. (2006).

Figure 2

Emerging molecular mechanisms of presynaptic plasticity. (a) Different forms of axonal structural plasticity. (Left) Growth: Inhibitory axon (green) form a contact on a hippocampal pyramidal cell dendrite (red). Arrow indicates the location of a future bouton. Modified from Wierenga et al. (2008). (Middle) Remodeling: GABAergic boutons can be stable (light-blue arrowheads), gained (yellow arrowheads), or lost (orange arrowheads). Modified from Schuemann et al. (2013). Images collected from organotypic hippocampal slice cultures using time-lapse, two-photon microscopy. (Right) Vesicle cloud redistribution: Synaptic vesicle (yellow) number, density, proximity to, and priming or docking state at the AZ(gray) can contribute to P_r. Cytomatrix filaments (red and blue) may also help regulate P_r. Modified from Fernández-Busnadiego et al. (2013). Data collected from cerebrocortical synaptosomes by way of cryo-electron microscopy. (b) Ribosomes in presynaptic boutons. (Left and top-right) Dual-STORM imaging of CB₁ receptors delineating two GABAergic boutons (blue) and 5.8S ribosomal rRNA (green) in acute hippocampal slices. Three-dimensional (3D) reconstructed boutons shown at right. Arrowheads indicate the two boutons. Dotted line in left panel outlines CA1 pyramidal cell soma. From Younts et al. (2016). (Bottom-right) presynaptic ribosomes (pink arrow) revealed by immunogold electron microscopy on retinal ganglion cell axon in the superior colliculus. Modified from Shigeoka et al. (2016). (c) (Left) Model of synaptic nanocolumn based on data collected by 3D-STORM revealing alignment of presynaptic and postsynaptic molecules. Shown presynaptically are synaptic vesicles, AZ proteins RIM1/2 (red) and Munc13 (green). Shown postsynaptically are glutamate receptors (orange), PSD-95 (blue), and actin (gray). The green tube highlights the nanocolumn. Modified from Tang et al. (2016). (Right) Schematic representation of the nanocolumn and its modulation. Plasticity can result from changes in presynaptic vesicle or cytomatrix filament clustering or changes in the density or proximity of VGCCs to the active zone. Adapted from Glebov et al. (2017). Abbreviations: AZ, active zone; P_r, probability of release; PSD, postsynaptic density; RIM, Rab-interacting proteins; STORM, Stochastic optical reconstruction microscopy; VGCC, voltage-gated Ca²⁺ channel.

Figure 3

Long-term presynaptic plasticity modifies short-term plasticity and synaptic filtering. (a) PreLTP and preLTD can shift P_r of individual terminals between low, medium, and high modes. (b) Schematic EPSCs resulting from five input pulses at relatively low and high frequencies across each P_r. (c) Schematic depicting synaptic filtering of excitation across each P_r. Low-, medium-, and high-P_r synapses can respectively exhibit high-pass, band-pass, and low-pass filtering. The amplitude ratio of P5 to P1 as a function of input frequency is shown. X indicates low frequency. O indicates high frequency. Long-term presynaptic plasticity can shift the range and type of filtering at a given synapse. Abbreviations: EPSC, excitatory postsynaptic current; P5/P1, pulse 5/pulse 1; P_r, release probability; preLTD, presynaptic long-term depression; preLTP, presynaptic long-term potentiation.