PSYC 3800: Mitdterm 2 Review - Synaptic Communication (Chapter 5)

Nerve Cell

The elementary signaling unit

Charles Sherrington

Coined the term ‘synapse’

~1000

How many connections does the average neuron form?

~10,000

How many neurons does one neuron typically receive input from?

10^14

How many synapses in the brain/body?

10^11

How many neurons in the brain/body?

• Electrical synapse: Two neurites are connected by a gap junction with channels comprised of connexons that allow direct flow of ions from one neuron to another

• Chemical synapse: Two neurons meet at a synapse where one (presynaptic) releases neurotransmitters stored in synaptic vesicles into the synaptic cleft where they are uptaken by the postsynaptic neuron OR presynaptic autoreceptors

What are the two types of synapses in the brain?

Connexons

Protein channel structures that form gap junctions which allow direct electrical communication between neurons

• Electrical synapses are typically found between cells in visceral organs

• e.g., Heart, Smooth muscle

• also in crustaceans

Allow for fast, synchronized and widespread activation which is essential for functions such as digestion & heartbeat.

In crustaceans, electrical synapses enable rapid, simultaneous activation of neurons, allowing quick escape responses to predators or threats

Where are electrical synapses typically found and why?

Edwin Furshpan & David Potter

Discovered electrical synapses

At gap junctions

Where does electrical signaling occur in the CNS?

Astrocytes and glial cells form gap junctions using their cellular processes (extensions). Processes extend outward and make contact with the processes of other neighboring cells. At contact points, connexin proteins assemble into connexons, which align with and dock with connexons of adjacent cell to form gap junctions which allow direct intercellular communication

How so Astrocytes and glial cells form gap junctions?

Gap Junction

The channel that connects two neurons at an electrical synapse.

• Comprised of two Connexon units, each of which is comprised of 6 connexin proteins

• Allow for direct communication between cells (intercellular communication) → can be between Astrocytes or neurons

• Calcium waves/tsunami (since Astrocytes do not fire action potentials, use Ca2+ to communicate & signal one another)

• ATP transfer (signaling molecule)

Form interconnected networks that allow direct intercellular communication and activity coordination across many cells.

How are gap junctions used by Astrocytes?

• Connect cytoplasm of two neurons to form electrical synapses that allow direct, rapid transmission of electrical signals

• Produce PSPs (although the signals passed are smaller than action potentials, can summate with other inputs to reach threshold and trigger an action potentials)

• allow synchronization of neuronal firing because permit direct, rapid, and bidirectional flow of current between neurons causing simultaneous depolarization

How are gap junctions used by neurons?

Signals produced by electrical synapses are small (not large enough to trigger an action potential on its own) → small PSPs

• However, because transmission is direct, rapid and bidirectional, multiple PSPs from adjacent cells summate to create a depolarization large enough to trigger an action potential, enabling synchronized neuronal firing

What is the downside of electrical synapses and how can it be overcome?

True; electrical synapses fire at the same time because they are connected by gap junctions.

• When neuron A fires, some current flows directly into neuron B, which therefore gets depolarized (more +) immediately

• If depolarization is sufficient enough to reach threshold, AP fires → simultaneous depolarization & synchronized firing

T or F: neurons connected by electrical synapses fire at the same time

• Presynaptic neuron fires: action potential is activated → influx of Na+, inside = depolarized

• Current spreads easily through gap junctions into neighboring/adjacent neurons (low resistance, high conductance)

• Neighboring post-synaptic neurons are depolarized: small PSPs → if threshold reached, AP generated

• Synchronization: since many neurons are connected, each sends small depolarizations that add together (summate) and reach threshold/fire at similar times

How does an electrical synapses trigger an action potential?

• Speed: rapid transmission of signals compared to chemical synapses

• Bi-directional signaling (gap junctions form symmetrical channels between neurons allowing current to flow in either direction depending on the voltage difference between cells)

• High Threshold to Fire, but fire simultaneously: allows neurons to produce stronger, more reliable, coordinated signals and improve transmission speed

• Metabolic Signals: don’t just let electrical current, pass:

  • Small molecules

  • Metabolites

  • Second messengers

Allow coordination and communication of metabolic activity

What are the pros of electrical synapses?

Electrotonically Coupled

When two cells are connected via gap junctions (connexons) allowing electrical current to flow directly between them

Otto Loewi

Found that the electrical stimulation of a frog heart muscle released a chemical (Vagussroff, AKA ACh). This chemical could mimic the effects of electrical stimulation in other tissues

• Can mediate excitatory Or inhibitory signaling (more flexible)

• More complex - plasticity

• Amplify signals (regenerate at every synapse)

What are the pros of chemical synapses?

Postsynaptic density (PSD)

A protein-dense region located on the postsynaptic membrane of a chemical synapse; contains receptors, ion channels, and signaling molecules (Chemical messengers)

Gray’s type I (Asymmetrical): Excitatory

• Thick PSD, thinner pre-synaptic density

• Lots of receptors & strong signaling machinery

• EPSP

Gray’s Type II (Symmetrical): Inhibitory

• Thin PSD; pre- and postsynaptic sides look similar

• Different receptor types

• IPSP

How does PSD reflect the type of synapse?

Gray’s type I synapse

• Asymmetrical synapse (thick PSD)

• Typically excitatory

• EPSP

Gray’s type II synapse

• Symmetrical synapse (similar Pre- and postsynaptic densities)

• Typically inhibitory

• IPSP

• Axodendritic

• Axosomatic

• Axoaxonic

• Dendrodendritic

What are the 4 synaptic arrangements in the CNS?

Amino acids

Small organic molecules that contain at least one nitrogen atom and mediate fast synaptic transmission

• Amino Acids

• Biogenic Amines

• Peptides

What are the 3 classes of NTs?

• GABA (Inhibitory)

• Glutamate (Excitatory)

• Glycine (Inhibitory)

• Aspartate (excitatory)

What are the 4 main amino acid NTs?

Neuromuscular Junction

A specialized chemical synapse at which a motor neuron terminal meets skeletal muscle fibers; facilitates nerve-to-muscle communication

• Studies of this synapse type have helped establish principles of synaptic transmission

• High clinical relevance & easy accessibility

1. NT molecules are synthesized and concentrated in synaptic vesicles

2. Impulse arrives in presynaptic axon terminal

3. Voltage-gated Ca2+ channels open and increase local Ca2+ concentrations

4. Synaptic vesicle membranes fuse with presynaptic membrane and spill contents into synaptic cleft

5. NT diffuses across synaptic cleft

6. NT binds to receptors in PSD

7. ‘Ionotropic” receptors are NT-gated (or ligand-gated) channels that can generate PSPs

8. ‘Metabotropic” receptors are coupled G-proteins to trigger biochemical changes in postsynaptic neuron

9. Actions of NTs are terminated by enzymatic destruction or reuptake by presynaptic neurons or glial cells

AP → Ca2+ → release → bind → response → remove

What are the 9 steps of chemical synaptic transmission?

1. NT synthesis

2. Load NT into synaptic vesicles

3. Vesicles fuse to presynaptic terminal

4. NT spills into synaptic cleft (exocytosis)

5. Binds to postsynaptic receptors

6. Biochemical/Electrical response elicited in postsynaptic cell (excitation or inhibition)

7. Removal of NT from synaptic cleft

What are the 7 basic steps of neural communication?

GABA

What NT is synthesized from glutamate

Spinal cord

Where is Glycine prevalent?

In cells

Where is glutamate prevalent?

Biogenic Amines

Small organic molecules that contain at least one nitrogen atom, and have slower, modulatory effects at the synapse

• Dopamine (Da)

• Norepinephrine (Ne)

• Epinephrine (E)

• Serotonin (5-HT)

• Histamine (H)

What are the 5 main biogenic amine NTs?

• Da

• Ne

• E

What are the 3 catecholamines

Catecholamines

A division of biogenic amines made from Tyrosine;

Key roles in movement/reward, attention/arousal, and flight/fight

Indolamines

A division of biogenic amines that are synthesized from Trytophan.

Key roles in mood/sleep/emotion & sleep-wake cycle

Imidazoleamine

A division of biogenic amines made from histidine

Key function in wakefulness/arousal & sleep-wake regulation

Serotonin

What biogenic amine is an indoleamine?

Histamine

What biogenic amine is a imidazoleamine?

Peptides

A type of NT that are short amino acid chains stored in and released from secretory granules

• Dynorphin

• Enkephalins

What are the 2 main peptide NTs?

Dale’s Law

A single neuron always produces the same transmitter at every one of its synapses; now known to be incorrect (corelease)

Synthesized in axon terminal where they are loaded into synaptic vesicles

Where are small molecule NTs synthesized (amino acids & biogenic amines)?

Synthesized in the rough ER of the cell body, then processed in the Golgi and transported to the axon terminal

Where are peptide NTs synthesized?

To get substances into vesicles; each vesicle has 1000s of NT molecules

What is the role of transporters in neurons?

Ca2+

What ion drives the signal for NT release?

Proteins that control the movement, targeting, docking and fusion of vesicles in axon terminal.

What are trafficking proteins?

A group of synaptic vesicles that are stored away from the active sone and used as a backup supply of NT vesicles

• tethered to cytoskeleton

What is the reserve vesicle pool?

• Readily resealable pool (RRP)

• Recycling pool

• Reserve pool

What are the three types of vesicle pools?

<1%

What percentage of vesicles are docked?

85-90%

What percentage of vesicles are in the reserve pool?

10-15%

What percentage of vesicles are in the recycling pool?

A group of synaptic vesicles that continuously cycle between releasing NT and being refilled for reuse during normal synaptic activity

What is the recycling vesicle pool?

Exocytosis

Process by which vesicles release their contents

• Localized increases in Ca2+ concentration inside the cell

  • As axon terminal becomes depolarized, voltage-dependent Ca2+ channels on the presynaptic neuron open

  • At rest, the concentration of Ca2+ inside the cell is very low, therefore there is a large driving force propelling Ca2+ inward

Ca2+ is the signal for NT release

What causes exocytosis?

“Fusion machine”

A set of proteins— primarily SNARE proteins & synaptotagmin— that mediate vesicle fusion

• SNARE complexes

• Synaptotagmin

What are the two types of proteins that mediate vesicle fusion?

SNARE proteins

Proteins that bring vesicles and membrane together to drive membrane fusion

• v-SNARE (on vesicle)

• t-SNARE (on target/presynaptic membrane)

What are the 2 types of SNARE proteins?

• synaptobrevin

The v-SNARE in synaptic vesicles

• SNAP-25

• Syntaxin

The t-SNAREs on the presynaptic neuron

• They ‘zip’ together, pulling the visible and membrane close enough to fuse

What happens when SNARE proteins interact?

Synaptotagmin

A protein on vesicles that act as Ca2+ sensors; C2A & C2B domains bind to Ca2+ ions allowing synaptotagmin to detect calcium influx

• SNAREs drive fusion

• Synaptotagmin triggers fusion in response to Ca2+ influx

What is the key difference between SNAREs and synaptotagmin?

• Docking

• Fusion

What are the 2 main steps of exocytosis?

• Weakly to snare proteins & PIP2 (phospholipid component of membrane)

• This keeps vesicle ‘docked’ in place

At low levels of intracellular Ca2+, where do C2 domains of synaptotagmin bind?

• As intracellular concentrations of Ca2+ increase, Ca2+ binds to C2 domain of synaptotagmin causing conformational changes in SNARE proteins and synaptotagmin

• Synaptotagmin can now bind more strongly with PIP2 (membrane) & interact more strongly with SNARE proteins

• Leads to fusion of vesicle to cell membrane creating a pore

Synaptotagmin interacts with SNARE proteins to couple Ca²⁺ influx to vesicle fusion, ensuring that neurotransmitter release occurs rapidly and only when intracellular Ca²⁺ levels rise.

At high levels of intracellular Ca2+, where do C2 domains of synaptotagmin bind?

• less localized than amino acids and biogenic amines

  • Typically not in active zones

• Tend to require higher levels of stimulation (high frequency)

What is different with the release of peptide NTs?

• Ionotropic (ligand-gated)

• Metabotropic (G-coupled)

• Autoreceptors

What are the 3 receptor varieties?

Ionotropic receptors

Also known as ligand-gated or transmitter-gated ion channels;

• Direct gating: receptors are a part of the channel protein

• Many composed of 5 subunits

  • Each subunit though to consist of 4 membrane spanning alpha-helices

• When specific NT or other ligand binds to receptor, channel opens

Ionotropic receptors

What type of receptor channels are direct gates?

GPCR (G protein-coupled receptors)

What type of receptor channels are indirect gates?

EPSP

Transient post-synaptic membrane depolarization by presynaptic release of NTs

IPSP

Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of NTs

• Bind to receptor proteins

• Activate small proteins (g-protein)

• Activate effector proteins and can

  • Gate channel, &/or

  • Second messenger systems

Steps of NT action on GPCRs:

Metabotropic receptors

Receptors where the actual receptor is separate from the channel it regulates

• Involves indirect gating

• NT activates GTP-binding proteins

• Second messenger cascade

  • May open or close phorphylation gated channels

Typical receptor has a single subunit with seven alpha-helices → binding region = within the pore of the membrane

• Fast-acting

• Relatively transient responses (msec)

• Found in systems that require rapid responses (e.g., reflexes)

Characteristics of an ionotropic receptor

• Slower synaptic action (seconds-minutes

• Alter excitability of neurons and strength of synaptic connections

• Crucial for learning

Characteristics of a metabotropic receptor

Autoreceptors

Receptors located of the pre-synaptic neuron that are senticve to the NT released by the presynaptic terminal;

• Act as a safety to reduce release wen levels are high in synaptic cleft (autoregulation)

• Typically GPCRs with second messenger mediated functions

• Inhibit NT release or synthesis in presynaptic neuron

• Are membrane-spanning proteins (region exposed to external environment recognizes and bind to NT)

• Carry out effector functions within the target cell

  • Typically opening and closing of channels

What are the 2 biochemical features all NT receptors have in common?

• If left in synaptic cleft for prolonged periods , would prevent new signals from getting through and would cause desensitization

Why is timely removal of NTs from the synaptic cleft so important?

Desensitization of receptor channels

Phenomenon, where, despite signal, transmitter gated channels remain closed

• Diffusion

• Enzymatic Degradation

• Reuptake

What are the 3 mechanisms of NT removal from the synaptic cleft?

Diffusion

A process of removing NTs from the synaptic cleft;

• Passive movement of NTs out of the synaptic cleft, down their concentration gradient, into extracellular environment

• Occurs away from the synapse >100microns away

• Receptors on Glial cells act as transporters for uptake

Ezymatic degradation

A mechanism of NT removal from the synaptic cleft, in which NTs are broken down into inactive components/molecules

• can occur in the cleft or following reuptake into the cytoplasm of the presynaptic cell

Reuptake

A mechanism of NT removal from the synaptic cleft where transporter molecules on neurons or glia bring NTs back into presynaptic cell where they are degraded or recycled in vesicles

• most common method of removal

Many psychoactive drugs are linked to reuptake because many of the, change how long NTs stay in synaptic cleft by targeting reuptake transporters

• Reuptake inhibition

• Reuptake reversal

Why are psychoactive drugs linked to NT reuptake?

• Glutamate subtype

• ‘Other’ subtypes- NE, DA, GABA, etc.

What are the 2 types of reuptake transporters?

• EAAT (remove glutamate from synaptic cleft)

• GLUT ( transport glutamate into vesicles)

What are the two types of Glutamate reuptake transporters?

• 6-8 transmembrane proteins

• Require co-transport of Na+ and counter-transport of K+

• Some are Na+ independent

What are the main characteristics of glutamate transporters?

• 12 membrane-spanning proteins

• Require co-transport of Na+ and Cl-

What are the main characteristics of ‘other subtype’ transporters?

Neuropharmacology

The effect of drugs on NS tissue

Agonists

Drugs that increase or facilitate activity of a NT

Antagonist

Drugs that decrease or inhibit the activity of a NT

Receptor antagonists

Inhibitors of NT receptors