Module 3 - Synaptic Transmission Flashcards
L3.1 - Define electrical and chemical synapses
Electrical synapses happen between few (1%) neurons in the brain. Compared to chemical synapses, they’re faster, bidirectional, has direct transfer of current that maintains their “sign” (de/hyper polarization), they are able to synchronize (no delay in firing), and can vary in strength depending on the opening/closing of gap junctions.
In electrical synapses, the gap junctions are formed by 2 connexons (containing 6 connexins each), which work as a pore between 2 neurons and allows the current to pass between the two neurons directly.
Chemical synapses work by releasing NTs based on APs, where receptors will respond, which leads to current changes or changes in gene transcription.
The chemical synapse can be recognized by the active zone (here there are many vesicles) and the postsynaptic density (receptors)
L3.1 - Explain mechanisms of excitatory and inhibitory neurotransmission
In inhibitory neurotransmission, we decrease the probability of exciting an AP by decreasing the MP. In excitatory signaling we increase the probability.
An excitatory neurotransmitter will open a channel in which the reversal potential (equilibrium potential for ions reversal potential of an ion channel is the potential where the electrical current through the channel is zero) will be over the threshold (so that we can get there) – is for glutamate 0 mV.
For inhibitory NTs we want a reversal potential lower than the threshold
The ions equilibrium potential can therefore dictate if the receptor will give depolarization or hyperpolarization – this is seen change when the EQ change from being above the threshold in the embryonic state to being below the threshold in the adult stage. As it’s the only ion permeable in GABA receptors, it change the effect of GABA signaling.
Glutamate receptor are excitatory by being permeable to Na+, K+ (NMDA and Kainate) and Ca2+, Na+, K+ (NMDA)
L3.1 - Describe summation of EPSPs and IPSPs
Summation of EPSPs generally lead to the generation of an AP if there is a temporal and/or spatial summation between them at the axon initial segment. IPSPs lowers the membrane potential and can in certain cases stop EPSPs from forming action potentials through shunting inhibition or by cancelling out the charge.
If the EPSP is too far away from the axon initial segment, there might be a loss current due to leaks.
L3.1 - Explain presynaptic release mechanisms (SNAREs, synaptotagmin etc.)
When an AP enters the presynaptic space, P/Q ca2+ channels open and allow in Ca2+, which mobalized the cells towards the membrane.
As the vesicle approaches the membrane, the SNARE proteins form a complex and drags the vesicle close to the membrane. This is possible, as synaptobrevin (a SNARE protein) is found on the vesicle, and other SNARE proteins are membrane associated. Synaptotagmin (bound to the SNARE complex) is thought to operate as a ca2+ sensor and allows fusion by bending the membrane slightly up when the ca2+ levels are high enough (ca2+ binds to synaptotagmin). Fusion requires energy, as both membranes are negatively charged, but when ca2+ binds, this negative change is less and both the membrane and vesicle will be attracted to this charge.
After fusion, NSF and SNAP helps to disassemble the SNARE complex, which requires ATP
Ca2+ comes in from receptors close to the point where the vesicle binds is only released in nanodomains
L3.1 - Explain recycling of vesicles
After fusion, the vesicles go are recycled in the endosome and are re-formed through budding, which is where they’re starting to form back into vesicles. In endocytosis, clathrin helps the vesicles to get internalized and fuse with the endosome, which will create new vesicles that can be filled by NTs
L3.1 - Describe trans-synaptic protein pairing
Some proteins are “paired” across the synapse such as Neurexin and Neuroligin. This forms a transsynaptic nanocolumn. Initially thought to be a structural thing, but it turns out the pairs are signaling back and forth. It might specify synaptic identity or help synapse forming.
L3.1 - Explain synaptogenesis and synaptic pruning
Synaptogenesis (the creation of synapses) happens in the embryonic and postnatal period and likely rely on trans-synaptic protein pairing. Synaptic pruning takes place during the teenage years, where we go from 10^15 to 10^14 neurons.
L3.2 - Define a neurotransmitter
A neurotransmitter has 3 requirements:
Needs to be present in the neuron
Liberated as a result of action potentials
Activate receptors from the post synaptic cell
L3.2 - Describe acetylcholine as a neurotransmitter and the cholinergic synapse
Acetylcholine is a small molecule NT and is used in muscles and has both nicotine and muscarine receptors (ion or GPCRs)
Nicotine receptors have 5 subunits (2 are alpha) and are decreased in Myasthenia Gravis. They are activated by nicotine and blocked by curare. They’re permeable to Na+ and K+ and found at the NMJ.
L3.2 - Describe glutamate as a neurotransmitter and the glutamatergic synapse
Glutamate is in 80% of synapses are is excitatory. AMPA, NMDA and Kainate receptors are used (NA/K for all and Ca2+ for NMDA).
NMDA is a coincidence detector (requires depolarization, glutamate and glycine/D-serine to be present for activation)
Takes part in excitotoxicity after stroke (causes more depolarization)
L3.2 - Describe GABA as a neurotransmitter and the GABAergic synapse
GABA is inhibitory and has GABAa (ionotripic, cl- permeable, fast) and GABAb (GPCR, K+ permeable, slow) receptors.
L3.2 - Define wiring transmission versus volume transmission
Wiring transmission is created to make localized communications from cell to cell and volume transmission is where NTs are released mid-axon to a larger space. Wiring transmission uses classic NTs where volume transmission is more in catecholamine signaling.
L3.2 - Describe the monoaminergic systems (serotonin, dopamine and noradrenaline)
Monoamines = serotonin + catecholamines
L3.2 - Define main receptor types (ligand-gated ion channels, enzyme-linked receptors, G-protein coupled receptors, intracellular receptors)
Channel linked receptors (ligand gated) work by opening or closing the pore of the channel (ionotropic receptors)
Enzyme linked receptors (like tyrosine kinase) causes phosphorylation of downstream targets
G-protein coupled receptors can cause downstream signaling effects, but through the 2nd messenger
Intracellular receptors are inside the neuron and will lead to protein translocation and regulation of transcription (e.g. retinoid receptor)
L3.2 - Describe intracellular signaling cascades and nuclear signaling in neurons (second messengers, protein kinases, protein phosphatases, nuclear signaling)
A GCPR will have a 2nd messenger (g-protein), that in excitatory states can activate the protein kinases (will phosphorylate proteins). Protein phosphatases de-phosphorylates proteins and can also be triggered in neuronal cascades.
Typical second messengers (will activate effectors) are: ca2+ (activate calmodulin), cyclic nucleotides (activate protein kinases) and membrane lipids (activate protein kinases or releases intracellular ca2+ stores)
Important kinases are listed below + Ca2+/calmodulin-dependent protein kinase, type II (important in early phases of LTP) + MAKP + ERK (both activated by phosphorylation of other kinases)
Nuclear signaling (signaling to the nucleus) has to do with changes to the transcription, which can be modulated by CREB –> can be activated by multiple signaling pathways
L3.2 - Describe the ultrastructure of a chemical synapse
L3.2 - Describe the relationship between morphologically “docked” and functionally “primed” synaptic vesicles.
The relationship is still not well understood. We know that all primed vesicles (vesicles that can fuse and lead to postsynaptic events) need to be docked (structural term for a vesicle touching the membrane). It seems that some of the docked vesicles become primed but not all, as not all docked vesicles fuse.
Without Munc-13, we known that vesicles neither dock or get released, proving a correlation between the docking and priming principles. The number of primed and docked vesicles correlate.
L3.4 - Explain and interpret measurements of synaptic transmission
Synaptic events can be measured by looking a EPSCs (currents are better than potentials, as we better can understand the fluctuations). Larger summations can lead to action potentials, which will propagate down the axon.
The size of the EPSC will depend on the number of NTs released, which is proportional to the number of vesicles (N), their release probability (p) and the level of NT in them along with postsynaptic propperties (Q).
L3.4 - Define quantal parameters of the synapse: N, P and Q
N= number of release sites (structural concept)
P= probability that a release site releases a vesicle (whether or not the release site is occupied – functional term)
Q= quantal size (postsynaptic response per released vesicle – includes n of receptors, receptor sensitivity, number of NTs in the vesicle) – mainly a postsynaptic measure
I is the response to an AP (the eEPSP) and Q to one vesicle fusing (mEPSP)
Maximal variance in the response is when P is 0.5
As synaptic transmission is stochastic, p is just an overall measure of likelihood and shows that there is no 1:1 relationship in APs fired and vesicle release, which is otherwise taught
L3.4 - Define vesicle priming and the Readily Releasable Pool
Primed vesicles can be part of the RRP and priming is mediated by Munc13, Mucn18, SNARE, where the vesicles are bound to the membrane. The RRP are the vesicles that potentially can be released by an AP and will be refilled over time. The RRP = N when probability of N being occupied = 1, because they need to have a release site (N) and be docked there (p of being occupied). In short, RRP = N * P of occupation.
RPP is easier to measure then N, so it’s often more used.
L3.4 - Define short-term synaptic depression and short-term synaptic facilitation
Both processes last ms-sec max.
Short term plasticity is a change in synaptic strength due to rapid stimulation. This can include post synaptic features (receptors being saturated) but presynaptic features like P changing due to ca2+ is more relevant.
Short term depression: a decrease in synaptic output when rapidly stimulating due to an initially high p, that leads to a depletion of the RRP, which has a slow refilling.
Short term facilitation: an increase in synaptic output due to an initially low p, that increases with the accumulation of ca2+ or increase in the RRP due to rapid stimulation.
L3.4 - Explain possible mechanisms for short-term synaptic depression and facilitation
Some neurons might be more likely to go into synaptic facilitation, which is because ca2+ channels are further from the release site (Mucn13b driven) leads to less ca2+ immediately getting clogged up (or buffered) and therefore an overall lower p, which has the ability to increase over time (why release increases as well – p increases). This is possible, as there is a quick refilling of the RRP. Synaptotagmin-7 might mediate the increase in response by binding ca2+.
The neurons more driven by synaptic depression has Munc13a-mediated ca2+ channels close to the release sites, leading to an immediate strong release and then nothing. This could be changed to a facilitating synapse if ca2+ is decreased.
L3.5 - Define short and long-term plasticity and explain the molecular mechanisms
Short term plasticity generally lasts minutes, where long term is hours. It’s a modulation in the synaptic strength, which can be measured by larger EPSCs. One example is sensitization, where the strength of the synapse is increased by having modulatory inputs from seretonine.
In the short term, sensitization works in the aplysia by having a second sensory neuron synapse onto the primary sensory neuron -> seretonine is releases -> GPCR activates cAMP -> cAMP breaks PKA into catalytic and regulatory subunits -> catalytic subunits will block K+ channels to make the synaptic response stronger, by letting in more ca2+
In the long term, CREB is phosphorylated by PKA, which will upregulate the production of Ubiquitin hydrolase, which degenerates the regulatory subunits of PKA, so the catalytic subunits can block K+ channels for an extended period of time. This ensures that seretonine is no longer needed to facilitate the increase in vesicle release.
L3.5 - Explain Long Term Potentiation (LTP) at hippocampal synapses, including input specificity, associativity and the role of postsynaptic NMDA receptors in the induction of LTP
LTP is the long-term potentiation between two synapses (it’s synapse specific)
In order to induce LTP you need the cell to fire together - restricted to input paired with postsynaptic depolarization – (presyn slightly before post synapse) input specificity
Associativity: the LTP can spread if a synapse close by (max 50 micrometer onto the same neuron) fires at the same time. A burst of stimulation is in this case not necessary if it’s present in the neighbor.
LTP relies on NMDA receptors, as a Ca2+ influx is required to activate CAMKII and PKC, which will phosprylate AMPA receptors (makes them more sensitive) and to activate synaptotagmins, which will bring new AMPA receptors to the surface
LTP also gives more dentritic spines on the postsynapse
L3.5 - Explain Long Term Depression (LTD) at hippocampal and cerebellar synapses
Long term depression is the decrease in synaptic transmission efficacy
Slow and small Ca2+ influxes will activate protein phosphates, which will internalize AMPA receptors through an unexplained clatherin depended process
It can also happen at the cerebellar synapse, where it’s important in motor control. Here paralelle fibers and climbing fibers are involved. NMDA receptors don’t play a role, but ca2+ is still implicated in the process.
Here the ca2+ can activate PKC, which phosphorylates AMPA. This leads to an internalization and decrease in response. The Ca2+ is released from climbing fibers through voltage gated channels and in parallel fibers through phospholipase C –> PIP2 = DAG + H+ + Ip3 –> intracellular ca2+ stores.
L3.5 - Describe Spike Timing Dependent plasticity
Potentiation is only possible if the post synapse fires after the presynapse. If the post synapse fires first, long term depression will be seen.
Processes can be used in treating incomplete spinal injury –> trigger upper motor neurons with TMS prior to lower motor neurons with peripheral nerve stimulation
L3.6 - Describe the classical roles of astrocytes (K+ buffering and reuptake of neurotransmitter)
Classically, astrocytes were seen as the maid of the brain – they buffer K+ concentrations locally and diffuse it to decrease the risk of hyperexcitability or epilepsy.
Additionally, they can take up NTs like glutamate and GABA to 1) stop the signaling and 2) to break the NT down and recycle it (GABA glutamate glutamine). Their uptake of NTs can prevent hyperexcitability.
They are territorial and communicate via gap junctions to each other. They can also regulate blood flow through their endfeet at the brain vessels.
L3.6 - Describe the concept of the tripartite synapse (see Purves, box 5, p. 102)
This is a normal synapse where an astrocyte is also present. Astrocytes have receptors that can respond to NTs and through increased Ca2+ levels can release gliotransmitters to communicate to other cells.
L3.6 - Describe the response of astrocytes to neuronal activity (calcium release)
Neuronal signaling will lead to increase in intracellular calcium for the astrocyte, which can cause release of gliotransmitters to support the synapse
L3.6 - Define the term gliotransmitter and explain its significance
Gliotransmitters are the transmitters released by glial cells (similar to neurotransmitters), that allows the cell to signal to other cells.
Astrocytes are known to release purines in response to glutamate, which can affect A_2A adenosine receptors on the neuron to release more glutamate affect presynaptic signaling and ensures less failure of signals
Gliotransmitter release glutamate in response to GABA inputs, which also can lead to less failure in synaptic transmission between neurons plays a role in synaptic plasticity
Astrocytes deliver D-serine to the NNMDA receptors which are necessary for their function astrocytes are necessary in LTP
L3.6 - Explain the role of astrocytes in short-term and long-term plasticity of the tripartite synapse
- Glutamate is released from astrocytes in response to presynaptic neurons sending out GABA, which can lead to less failure in synaptic transmission between neurons –> plays a role in synaptic plasticity OR glutamate is sensed by the astrocyte, which releases purines that can activate A2a receptors and up-regulate glutamate release
- Endocannabinoid signaling from a post synapse allows astrocytes deliver D-serine to the NMDA receptors which are necessary for their function –> astrocytes are necessary in LTP, which otherwise is supported by the pre-synapse releasing glutamate in bursts
L3.7 - To explain selected disease mechanisms of the synapse, including genetic, misfolding and autoimmune diseases (only those examples that were mentioned at the lecture)
Genetic diseases of the synapse (Ex: SNAREopathies)
SNAREopathies can happen due to any mutation in the SNARE complex.
- A mutation in Munc 18 will cause neurodevelopmental disorder (Munc 18 is essential for the SNARE to develop) –> often de-novo and haploinsufficiency –> Dysfunctional SNARE will slow down all brain processes, decrease IQ and affect abilities to move properly
- A mutation in SNAP-25 will lead to an impaired interaction with synaptotagmin - synaptotagmin normally stops random release, which doesn’t work here –> here there is leaking but very little response to APs, as the RRP is being randomly released –> intellectual disability and hyperexcitability
- There are many SNARE proteins, each mutation can lead to a diverse phenotype
Misfolding diseases of the synapse (Ex: Alzheimer’s disease)
- Alzheimer’s disease has Neurofibrillar tangles inside the neuron (tau) and beta amyloid outside
- Amyloid Precursor Protein can either be broken down by ADAM10 or BACE1 –> ADAM10 doesn’t cause beta amyloid to be created, but BACE1 does. A little beta amyloid is good, but when there is too much, it decreases LTP. It’s believed that it’s the oligomers and not the plaques that are toxic, which is why most newly developed drugs don’t work (targets plaques)
** Autoimmune diseases of the synapse (Ex: Lambert Eaton myasthenic disease, Myasthenia gravis, Anti-NMDA receptor encephalitis)**
- Lambert Eaton myasthenic disease: AB against Ca2+ channels –> doesn’t affect brain, but will make NJMs unlikely to function. Treatment: immunosuppressants and K+ channel blockers
- Myasthenia gravis: AB against nicotine receptors (Ach) –> gives weakness in eyes, face and problems swallowing
treatment: immunosuppressants and Ach esterase blockers
- Anti-NMDAreceptor encephalitis: ABs against NMDA receptors –> correlates with teratomas, where there is a breakdown of the BBB, which allows the ABs into the CNS and can give psychological effect (hallucinations, but also fever, decreased breathing) -> demonic possession? Treatment: immunosuppressants
L3 (MISSING) - Describe structural and functional synaptic diversity
Structurally, synapses can differ in type (electrical or chemical) and can have different neurotransmitters and therefore different receptors. Synapses can occur as axo-dendritic, axo-somatic and axo-axonic. Some are excitatory (glutamate, Ach), inhibitory (GABA, glycine) or modulatory (monoamines: dopamine, serotonin and NE). Astrocytes can also have feet in the synapses to support then environment.
L3 (MISSING) - Describe morphological synaptic vesicle pools
Synaptic vesicles are formed from the endosome and are often portrayed as round with NTs in them, but they have a lot of surface proteins on them. Their morphology stays the same after endosome recycling, and they’re all the same size, which enables them to hold the same volume of NTs to have a more reliable release.
