Running to Stand Still: Ionotropic Receptor Dynamics at Central and Peripheral Synapses
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Keywords:
Silent synapse
Neurotransmitter receptor
Postsynaptic density
Active zone
Abstract Chemical synapses are among the most elaborate junctions existing between two cells, enabling communication between neurons through chemical neurotransmission within milliseconds. This fast rate of transmission is achieved through three subsynaptic compartments; the presynaptic bouton, the synaptic cleft and the postsynaptic junction. The presynaptic bouton packages neurotransmitters into synaptic vesicles then releases them into the synaptic cleft. Release of synaptic vesicles occurs through several distinct stages, coordinated by a group of specialised proteins. The postsynaptic density (PSD) has evolved into a complex neurotransmitter reception apparatus, which enables the postsynaptic terminal to modulate the downstream response to neurotransmitters. Following activation of receptors on the postsynaptic membrane, neurotransmitters are taken back up into the presynaptic bouton and repackaged into synaptic vesicles (SVs). The synaptic cleft contains proteins that ensure that active zone and PSD remain in proximity. These proteins are also required during synaptogenesis to ensure that the synapse forms properly. Key Concepts: There are three major structural components that define the synapse: the presynaptic bouton (also known as presynaptic terminal), postsynaptic junction (also known as postsynaptic terminal) and the synaptic cleft. The presynaptic bouton is responsible for packaging neurotransmitters into synaptic vesicles, then releasing their contents into the synaptic cleft in response to calcium influx. Synaptic vesicles are released at a specialised site within the presynaptic bouton known as the active zone. Synaptic vesicles are released by a process known as exocytosis through several distinct steps involving specialised proteins that form a highly interactive and dynamic protein complex at the site of synaptic vesicle release. Interpretation of the presynaptic message takes place at the postsynaptic membrane through transmembrane proteins called receptors. The postsynaptic density is situated adjacent to the postsynaptic membrane within the postsynaptic terminal, juxtaposed to the presynaptic active zone. The postsynaptic density is composed of receptors, scaffolding and adhesion proteins, kinases and phosphatases, as well as cytoskeletal elements, which are linked together to form macromolecular complexes. The postsynaptic density of excitatory synapses is thicker (more pronounced) than the postsynaptic density of inhibitory synapses. The synaptic cleft is a narrow space, approximately 20–30 nm wide situated between the presynaptic and the postsynaptic plasma membranes. The synaptic cleft is composed of proteinaceous and carbohydrate‐rich cell adhesion molecules.
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The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft. Across the synaptic cleft glutamate binds to both ion channels and metabotropic glutamate receptors at the postsynapse, which expedite downstream signalling in the neuron. The postsynaptic density, a highly specialized matrix, which is attached to the postsynaptic membrane, controls this downstream signalling. The postsynaptic density also resets the synapse after each synaptic firing. It is composed of numerous proteins including a family of Discs large associated protein 1, 2, 3 and 4 (DLGAP1-4) that act as scaffold proteins in the postsynaptic density. They link the glutamate receptors in the postsynaptic membrane to other glutamate receptors, to signalling proteins and to components of the cytoskeleton. With the central localisation in the postsynapse, the DLGAP family seems to play a vital role in synaptic scaling by regulating the turnover of both ionotropic and metabotropic glutamate receptors in response to synaptic activity. DLGAP family has been directly linked to a variety of psychological and neurological disorders. In this review we focus on the direct and indirect role of DLGAP family on schizophrenia as well as other brain diseases.
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Long-term depression
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Chemical neurotransmission occurs at specialized contacts where presynaptic neurotransmitter release machinery apposes clusters of postsynaptic neurotransmitter receptors and signaling molecules. A complex program underlies recruitment of pre- and postsynaptic proteins to sites of neuronal connection and enables the correct three-dimensional synaptic organization that underlies circuit processing and computation. To better study the developmental events of synaptogenesis in individual neurons, we need cell-type specific strategies to visualize the individual proteins at their endogenous levels at synapses. Though such strategies exist for a variety of presynaptic proteins, postsynaptic proteins remain less studied due to a paucity of reagents that allow visualization of endogenous individual postsynapses in a cell-type specific manner. To study excitatory postsynapses, we engineered dlg1[4K] , a conditional, epitope-tagged marker of the excitatory postsynaptic density in Drosophila . In combination with binary expression systems, dlg1[4K] effectively labels postsynaptic regions at both peripheral neuromuscular and central synapses in larvae and adults. Using dlg1[4K] , we find distinct rules govern the postsynaptic organization of different adult neuron classes, that multiple binary expression systems can concurrently label pre- and postsynaptic regions of synapses in a cell-type-specific manner, and for the first time, visualize neuronal DLG1 at the neuromuscular junction. These results validate a novel strategy for conditional postsynaptic labeling without the caveats of overexpression and demonstrate new principles of subsynaptic organization. The use of dlg1[4K] marks a notable advancement in studying cell-type specific synaptic organization in Drosophila and the first example of a general postsynaptic marker to complement existing presynaptic strategies.
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Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins. Here we use a genetic analysis in Drosophila to demonstrate that the serine threonine kinase Unc-51 acts in the presynaptic motoneuron to regulate the localization of the active zone protein Bruchpilot opposite to glutamate receptors at each synapse. In the absence of Unc-51, many glutamate receptor clusters are unapposed to Bruchpilot, and ultrastructural analysis demonstrates that fewer active zones contain dense body T-bars. In addition to the presence of these aberrant synapses, there is also a decrease in the density of all synapses. This decrease in synaptic density and abnormal active zone composition is associated with impaired evoked transmitter release. Mechanistically, Unc-51 inhibits the activity of the MAP kinase ERK to promote synaptic development. In the unc-51 mutant, increased ERK activity leads to the decrease in synaptic density and the absence of Bruchpilot from many synapses. Hence, activated ERK negatively regulates synapse formation, resulting in either the absence of active zones or the formation of active zones without their proper complement of proteins. The Unc-51-dependent inhibition of ERK activity provides a potential mechanism for synapse-specific control of active zone protein composition and release probability.
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Neurotransmitter receptor
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Postsynaptic density
Silent synapse
Long-term depression
Compartmentalization (fire protection)
Kainate receptor
Class C GPCR
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To determine their roles in the assembly of glutamatergic postsynaptic sites, we studied the distributions of NMDA- and AMPA-type glutamate receptors; the NMDA receptor-interacting proteins α-actinin-2, PSD-95, and chapsyn; and the PSD-95-associated protein GKAP during the development of hippocampal neurons in culture. NMDA receptors first formed nonsynaptic proximal dendrite shaft clusters within 2–5 d. AMPA receptors were diffuse at this stage and began to cluster on spines at 9–10 d. NMDA receptor clusters remained partially nonsynaptic and mainly distinct from AMPA receptor clusters until after 3 weeks in culture, when the two began to colocalize at spiny synaptic sites. Thus, the localization of NMDA and AMPA receptors must be regulated by different mechanisms. α-Actinin-2 colocalized with the NMDA receptor only at spiny synaptic clusters, but not at shaft nonsynaptic or synaptic clusters, suggesting a modulatory role in the anchoring of NMDA receptor at spines. PSD-95, chapsyn, and GKAP were present at some, but not all, nonsynaptic NMDA receptor clusters during the first 2 weeks, indicating that none is essential for NMDA receptor cluster formation. When NMDA receptor clusters became synaptic, PSD-95 and GKAP were always present, consistent with an essential function in synaptic localization of NMDA receptors. Furthermore, PSD-95 and GKAP clustered opposite presynaptic terminals several days before either NMDA or AMPA receptors clustered at these presumptive postsynaptic sites. These results suggest that synapse development proceeds by formation of a postsynaptic scaffold containing PSD-95 and GKAP in concert with presynaptic vesicle clustering, followed by regulated attachment of glutamate receptor subtypes to this scaffold.
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The assembly of glutamatergic postsynaptic densities (PSDs) seems to involve the gradual recruitment of molecular components from diffuse cellular pools. Whether the glutamate receptors themselves are needed to instruct the structural and molecular assembly of the PSD has hardly been addressed. Here, we engineered Drosophila neuromuscular junctions (NMJs) to express none or only drastically reduced amounts of their postsynaptic non-NMDA-type glutamate receptors. At such NMJs, principal synapse formation proceeded and presynaptic active zones showed normal composition and ultrastructure as well as proper glutamate release. At the postsynaptic site, initial steps of molecular and structural assembly took place as well. However, growth of the nascent PSDs to mature size was inhibited, and proteins normally excluded from PSD membranes remained at these apparently immature sites. Intriguingly, synaptic transmission as well as glutamate binding to glutamate receptors appeared dispensable for synapse maturation. Thus, our data suggest that incorporation of non-NMDA-type glutamate receptors and likely their protein-protein interactions with additional PSD components triggers a conversion from an initial to a mature stage of PSD assembly.
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Abstract Neuronal communication relies on rapid signalling via chemical synapses. Glutamate receptors mediate the majority of excitatory neurotransmission in the central nervous system. At excitatory synapses, glutamate is released and binds to a variety of glutamate receptors. Among these, α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors mediate most of the fast excitatory synaptic transmission. In addition, AMPA receptors play a critical role in the synaptic plasticity underlying learning and memory and neuronal development. When the regulation of synaptic expression of AMPA receptors goes awry, devastating neurological and neuropsychiatric diseases can occur. Since their cloning in the 1990s, much has been learned about the structure, assembly and trafficking of AMPA receptors. Exciting new advances in AMPA receptor research have offered unprecedented opportunities to understand dynamic regulation of AMPA receptor structure and function in brain. Key Concepts: AMPA receptors mediate fast glutamatergic synaptic transmission. Crystal structure of AMPA receptors shows unexpected domain organisation. Regulation of synaptic expression of AMPA receptors is highly dynamic. AMPA receptor modulation and/or trafficking mediates LTP. AMPA receptors are structurally diverse. Subunit composition of AMPA receptors varies at different synapses. Post‐translational modifications of AMPA receptors regulate trafficking and function. AMPA receptor dysfunction is involved in diseases.
Silent synapse
Long-term depression
SGK1
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Postsynaptic density
Neurotransmitter receptor
Active zone
Synaptic cleft
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