Mechanisms of Excitatory Synapse Maturation by Trans-
Synaptic Organizing Complexes
Hasan Arafat5th Year Medical Student
An-Najah University Nablus
Introduction-General TermsSynapse: specialized cell-cell adhesion contacts that mediate communication
within neural networks.Synaptic Transmission: the transfer of information at the synapse from one
neuron to another.Neurotransmitter: a chemical agent found stored in vesicles in the
presynaptic space, released upon stimulation to the synaptic cleft. Different neurotransmitters are used by different types of neurons.
Neuroscience : exploring the brain. Mark F. Bear, Barry W. Connors, Michael A. Paradiso. — Fourth edition.
How does a synapse form?• The CNS generates a huge number of synapses during its early
development• These synapses are later refined and sculpted to generate the
precise neural network of the adult brain• The first step of synapse formation is the recruitment of several
synaptic organizing proteins to the transsynaptic area• These proteins recruit synaptic vesicles to the presynaptic active
zone• NMDA receptors are recruited to the postsynaptic density• PSD-95 protein, a type of PDZ domain proteins, as a scaffold for
recruitment of these components • This generates silent synapses
Mechanisms of Excitatory Synapse Maturation by Trans-Synaptic Organizing Complexes. Samuel A. McMahon, Elva Diaz
What is AMPA receptor?● AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.● they are ligand-gated ion channels composed of combinations of four
separate subunits (GluA1-4).● These subunits differ from each other by their biophysical properties,
trafficking and binding partners● AMPARs are highly mobile proteins that undergo constitutive and
activity-dependent translocation to/ recycling at/ and removal from, synapses.
● Aberrant AMPAR trafficking is implicated in neurodegenerative diseases.
AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging. Jeremy M. Henley, Kevin A. Wilkinson
Neuroscience : exploring the brain. Mark F. Bear, Barry W. Connors, Michael A. Paradiso. — Fourth edition.
NMDA: N-methyl-D-aspartateNeuroscience : exploring the brain. Mark F. Bear, Barry W. Connors, Michael A. Paradiso. — Fourth edition.
The role of AMPA receptors1.These synapses can be strengthened or eliminated depending on their
activity2.Recruitment of AMPAs to the postsynaptic membrane augments
glutamatergic transmission3.This increases the activity of the synapse4.This is a critical step in excitatory synapse maturation
Mechanisms of Excitatory Synapse Maturation by Trans-Synaptic Organizing Complexes. Samuel A. McMahon, Elva Diaz
Neurexin Synaptic Organizing Complex• A multifaceted system of trans-synaptic development mechanisms:
• Neurexin interacts with neuroligin, they bind each other trans-synaptically, they influence synaptic differentiation and development
• Neurexins also interact with leucine-rich repeat transmembrane protein (LRRTMs), influencing presynaptic differentiation
• They are also the presynaptic binding partners of Clb1-GluD2, a structurally distinct signaling system that directs synapse formation
Neurexin-Neuroligin Recruitment of AMPA• Experiments showed that the application of glutamate at neurexin-
neuroligin contact sites induced GluA1-containing AMPA clustering.• Transfected neurons that express neuroligin showed increased synapse
formation only when glutamate is applied• GluA2-containing AMPA receptors clustering showed a different pattern• In hippocampal cells expressing neuroligin-1, the later showed
increased recruitment of GluA2 AMPAs in activity-independent pattern• GluA1-containing AMPAs were not recruited• CONCLUSION: recruitment is subunit-specific
LRRTMs influence of AMPA recruitment• LRRTMs were shown to induce synapse formation in non neuronal cells expressing them• LRRTMs were shown to induce presynaptic differentiation in contacting axons when
expressed in non neuronal cells, the same happened with neuroligin.• Co-culture of neuronal and non-neuronal cells expressing NMDA and LRRTMs lead to
spontaneous current• Knockout of LRRTM in hippocampal cells showed decreased GluA1-AMPAs and decreased
current.• mEPSC amplitude was modestly but insignificantly affected, while frequency was
unchanged• These data suggest that LRRTM primarily regulates synapse efficacy and plays a minor role
postsynaptic AMPA receptor density regulation.
Neurexin and Clb1-GluD2 complex• Neurexin acts as a presynaptic binding partner• The entire complex is responsible for synapse formation between
parallel fibers and Purkinje fibers in the cerebellum• A receptor antagonist to Clb1-GluD2 destabilized AMPA receptors• Expression of the complex in nonneuronal transfected cells, along with
GluA1, lead to glutamate-induced currents and mEPSC-like events• Knockout of Clb1-GluD2 leads to:
• reduced number of synapses and increased free spines• mEPSC amplitude is unchanged• Frequency reduced by 50%
• Still, it’s unknown whether Clb1-GluD2 is directly involved in AMPA recruitment
Mechanisms of Excitatory Synapse Maturation by Trans-Synaptic Organizing Complexes. Samuel A. McMahon, Elva Diaz
Synaptic Organizing Activity of Narp• Narp (neuronal activity-regulated pentraxin) receptor, also known as
NP2, a member of neuronal pentraxin family, mediates AMPA receptor clustering at synaptic contacts onto interneurons
• Narp is a secreted molecule, similar to NP1, a protein of the same family• NPR (neuronal pentraxin receptor), is an integral membrane protein• The three proteins form a hetero-oligomer, this allows the secreted
proteins to become membrane-bound
Testing the role of Narp/NP1• In transfected nonneuronal cells, the expression of neuroligin-1 was
required for the interaction between the hetero-oligomer and GluA• Knockout of Narp/NP1 reduced AMPA receptor-mediated transmission • This was tested in the retinogeniculate pathway• This lead to increased number of silent synapses during the eye-
refinement stage of retinogeniculate pathway development • CONCLUSION: Narp/NP1 complex is required for segregation of optic
fibers in the retinogeniculate pathway, which is an activity-dependent strengthening and elimination process
The Retinogeniculate PathwayNeuroscience : exploring the brain. Mark F. Bear, Barry W. Connors, Michael A. Paradiso. — Fourth edition.
Other Synaptic Organizing Complexes: ephrins/Eph• Ephrins and Eph complexes: axon guidance proteins, increasingly
appreciated for their role in synapse development• It was found that postsynaptic ephrinB2 interacts with presynaptic
EphB2 to stabilize AMPA in neuronal cells, while their knockout decreases the amplitude of mEPSC
• A decrease in amplitude suggests that the number of AMPA receptors was reduced
• CONCLUSION: ephrin/Eph is involved in AMPA recruitment
Other Synaptic Organizing Complexes: LAR• LAR: Leukocyte common Antigen Related Protein• Presynaptic LAR family protein tyrosine phosphatase receptors (PTRPs)
signal through the ligand NGL-3 to induce excitatory synapse development
• it has been shown to selectively cluster postsynaptic excitatory components, including GluA2 AMPA receptor subunits
• In the same study, it was found that frequency, but not amplitude, of mEPSCs was reduced with NGL-3 knockdown
• It’s still unclear whether this effect is direct or not
Other Synaptic Organizing Complexes: SALMs• SALMs: synaptic adhesion-like molecules• Coimmunoprecipitation experiments showed that SALM2 interacts with
both NMDA and AMPA receptors• This regulates the maturation of excitatory synapses• SALM5 knockdown reduces both amplitude and frequency of mEPSCs
and mIPSCs• This suggests that SALM5 promotes both excitatory and inhibitory
synaptic differentiation
Other Synaptic Organizing Complexes: SynDIG1• SynDIG1: synapse differentiation induced gene 1• A novel regulator of excitatory synapse maturation• SynDIG1 coimmunoprecipitates with AMPA receptor subunits in
heterologous cells• Knock-down of SynDIG1 in dissociated rat hippocampal neurons reduces
AMPA receptor content at developing synapses by ~50% • This was determined by immunocytochemistry and electrophysiology• SynDIG1 did not influence NMDA receptor containing synapses• CONCLUSION: SynDIG1 is a selective regulator of excitatory synapse
maturation
Mechanisms of Excitatory Synapse Maturation by Trans-Synaptic Organizing Complexes. Samuel A. McMahon, Elva Diaz
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