Mechanisms of excitatory synapse maturation by trans synaptic organizing complexes

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


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


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


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Mechanisms of excitatory synapse maturation by trans synaptic organizing complexes