Molecular organization and plasticity of the cytomatrix at the active zone

Regulated neurotransmitter release from presynaptic boutons is crucial for the functioning of chemical synapses, what in turn governs the functional performance of the nervous system. Release occurs at the active zone (AZ), a specialized region of the presynaptic plasma membrane that is defined by a unique and complex meshwork of proteins — the cytomatrix at the AZ (CAZ). Important functions of CAZ proteins include recruitment, docking and priming of synaptic vesicles as well as appropriate localization of voltage-gated calcium channels near vesicle docking sites. We will discuss recent progress in the understanding of the topological localization and the molecular functions of characteristic CAZ proteins as well as emerging molecular mechanisms underlying presynaptic plasticity that involve significant structural CAZ remodeling.

Introduction

Release of neurotransmitter from presynaptic boutons occurs at highly specialized regions of the presynaptic membrane: the active zone (AZ). At the AZ a series of membrane trafficking events, the synaptic vesicle (SV) cycle, underlies regulated release of neurotransmitter. Formally, the SV cycle can be divided into discrete steps including docking SVs to their release sites, priming of SVs to make them fusion competent and fusion of SVs with the AZ membrane allowing release of transmitter in response to Ca²⁺ influx through voltage-gated calcium channels (Ca_Vs). Compensatory endocytosis of the SV membrane right next to the AZ followed by recycling and refilling of the SV with neurotransmitter complete the cycle [1]. A complex electron-dense meshwork of proteins, the cytomatrix at the AZ (CAZ), is assembled at the presynaptic membrane and is thought to spatially and functionally organize key steps of neurotransmitter release including the organization of SV pools (recently reviewed in [2]), tethering, docking and priming of SVs [3, 4] (see also Box 1), the physical coupling of exocytic and endocytic machineries [5, 6••] or the localization of presynaptic Ca_Vs relative to SV docking sites (positional priming), which is an important determinant of release probability and presynaptic plasticity [7, 8]. Moreover, the CAZ proteins seem to be essential regulators of presynaptic assembly during synaptogenesis [9, 10, 11] and they are assumed to be involved in the recruitment and proper localization of cell adhesion molecules that mediate the proper alignment of the AZ with the postsynaptic neurotransmitter reception apparatus and determine synaptic specificity (for review see, e.g. [12, 13]).

The protein meshwork of the CAZ is organized by a small set of multi-domain scaffolding proteins including the Rab3-interacting molecules (RIMs), the RIM-binding proteins (RIM-BPs), Bassoon and Piccolo/Aczonin, the CAST/ELKS/Bruchpilot proteins, the Liprins-α and the UNC-13/Munc-13 proteins [11, 14, 15]. This review will discuss novel findings on the role of these proteins in organizing molecular structure and the functional plasticity of presynaptic neurotransmitter release sites.