Electrical vs Chemical Synapses

• Synapses serve as the location where a presynaptic axon meets a postsynaptic cell
• The presynaptic cell primarily sends information to the postsynaptic cell, with some feedback occurring from post- to presynaptic cell

Synapse Locations

• Synapses primarily form on the dendrites of a neuron
• Synapses also form with:
  • Cell body
  • Axon of other cells
  • Muscle cells
  • etc...

Synapse Classes

• Synapses are divided into two categories:
  • Electrical
  • Chemical

Electrical Synapses

• Electrical synapses are very uncommon
• They are found in some reflex circuits
• Pre- and postsynaptic cells are physically touching in electrical synapses
• Gap junctions from tunnels between cells allow ions to freely flow between cells
• Electrical synapses are similar to leak channels
• Electrical synapses show extremely fast signaling
• Ions freely and quickly flow from one cell to the other with no gating mechanism
• AP depolarization traveling down an axon directly carries over to the next cell
• Information passing between cells cannot be modulated in electrical synapses
• Electrical synapses are not as dynamic as chemical synapses

Chemical Synapses

• Almost all synapses in the nervous system are chemical synapses
• Pre- and postsynaptic cells are separated by a synaptic cleft
• There is a microscopic gap between cells, which are not physically touching in chemical synapses
• Neurotransmitters (NT) are released from the presynaptic cell
• NTs passively drift across the synaptic cleft
• NTs bind to NT receptors on the postsynaptic cell membrane
• NT receptors perform some type of cellular function when the NTs bind
  • Change in membrane potential
  • Protein activation
  • Gene expression
  • Etc.
• Chemical synapses are far slower than electrical synapses
  • They require NT release, drift, and receptor activation
• Chemical synapses are more dynamic in their signaling

Synaptic Transmission

Synaptic Terminal Structure

• The synaptic terminal structure is the end of an axon, also known as the axon bouton
• It is where information is converted from an electrical signal (AP) to a chemical signal (NT)
• Important structures for synaptic transmission include:
  • NT vesicles
  • SNARE complex proteins
  • Ca2+ voltage-gated channels
  • NT reuptake proteins

NT Vesicles

• NT vesicles are spheres made of the same material as the cellular membrane
• Spheres are densely filled with NTs
• Vesicles only contain one type of NT, and each vesicle contains the same amount of NTs
• Many NT vesicles are attached to the inside of the cellular membrane facing the synaptic cleft
• NT vesicles are primed and ready to be quickly released into the cleft
• Additional NT vesicles are not attached to the membrane, forming a reserve pool ready to be attached

SNARE Complex

• Vesicles are secured to the intracellular side of the membrane with SNARE complex proteins
• SNARE complex proteins include Soluble N-ethylmaleimide-Sensitive Factor Attachment Proteins (SNAP) Receptors
• SNARE complex proteins are responsible for:
  • Securing the vesicles to the membrane
  • Causing the NTs to be released into the synaptic cleft
• The SNARE complex is attached to the NT vesicles and membrane
• The vesicle is tightly secured against the inside of the cellular membrane
• Proteins are locked into a high stressed position
  • Containing potential energy used to release NTs
  • Like a clip held open, ready to clamp close
• Proteins are locked into high-stress position by Ca2+ sensor proteins
• When Ca2+ sensors detect Ca2+ in the cell, it will release from the SNARE complex
• Proteins clamp close and expel their stored energy
• The SNARE complex clamping closed applies force on the vesicle onto the cellular membrane
• SNARE complex forces the vesicle to fuse with the membrane, because they are made of the same material

Ca2+ Voltage-Gated Channels

• The synaptic terminal also contains Ca2+ voltage-gated channels
• Channels open very quickly when the membrane potential reaches ~0mV
• Channels have no inactivation mechanism

NT Reuptake Proteins

• Proteins embedded in the presynaptic cell membrane
• Bring NTs from the synaptic cleft back into the cell

Synaptic Transmission Steps

• Synaptic transmission terminal includes all the covered structures
• An AP travels down from the axon into the synaptic terminal
• The synaptic terminal greatly depolarizes, activating Ca2+ voltage-gated channels
• Ca2+ rushes into the synaptic terminal
• SNARE complex Ca2+ sensors detect an increase of Ca2+ in the cell
• The SNARE complex forces the NT vesicles to fuse with the membrane, forcing NTs into the synaptic cleft
• NTs drift across the synaptic cleft to bind to receptors on the postsynaptic cell, causing some type of cellular function
• NTs are cleared out of the synaptic cell, and the postsynaptic cell stops responding

Synaptic Cleft Clearance

• The nervous system will clear out the synaptic cleft of NTs quickly to prepare the synapse for the next wave of NTs
• Three methods for clearance are performed:
  • NT reuptake proteins
  • Degradation
  • Diffusion

NT Reuptake

• Proteins in the presynaptic cell bring NTs back into the cell
• NTs can be either:
  • Recycled to be reused
  • Broken down and components used for other processes

Degradation

• NTs are broken down by enzymes free-floating in the synaptic cleft, clearing out the NTs over time as they bind and break down the NTs

Diffusion

• NTs float out of the synaptic cleft and are taken up by neighboring astrocytes

Synaptic Cleft Clearance

• Clearance processes do not significantly affect NT signaling in a healthy system
• NTs are released in large quantities, so plenty of NTs will interact with a postsynaptic cell before NTs are cleared out

Receptors

NT Receptors

• NTs drift across the synaptic cleft to bind to NT receptors
• Receptors are proteins that are activated when a NT binds to their NT binding site
• Receptors are ligand-specific, and activated by only one specific NT
• Other substances activate receptors by mimicking a given NT
• NTs will resolutely bind and unbind with the receptors, repeatedly turning function on and off until all NTs are cleared from the synaptic cleft
• Two classes of NT receptors:
  • Ionotropic
  • GPCR

Ionotropic

• More simple of the two classes
• Ligand-gated ion channels
• Channels and NT binding sites are part of the same protein
• NT binding to the receptor results in a change in membrane potential
  • EPSP
  • IPSP
• Does not influence cellular functions in other ways

GPCR

• G-protein coupled receptor
• More complex of the two receptor classes
• Still has a NT binding site, but no ion channel built into the same protein
• When NTs bind to GPCRs, the G proteins detach from the internal side of the receptor protein
• G proteins activate other proteins to influence cellular processes
• G proteins can facilitate a wide range of cellular processes
  • Open ion channels, changing membrane
  • Influence other proteins
  • Influence gene expression

Ionotropic and GPCR Compared

• GPCRs can also influence membrane potential, but do not directly contain the ion channel as ionotropic receptors do
• GPCR will activate separate ion channels with the G protein
• Activating GPCR receptors is slower than ionotropic receptors
• GPCRs typically result in long-term influence of neural activity

Receptors

• The same NT can bind to a wide range of different receptors
• Each receptor type can have a wide range of effects on the cell
• The same NT can have inverse effects on cells based on the type of receptors that the postsynaptic cells have

DA in the Basal Ganglia

• The basal ganglia contains two pathways:
  • Direct Pathway: allows motor movements to happen
  • Indirect Pathway: prevents a motor movement from happening
• Each basal ganglia pathway contains different classes of dopamine (DA) receptors with inverse effects
  • Direct Pathway: D1-excitatory
  • Indirect Pathway: D2-inhibitory
• When DA is released in the basal ganglia, it will interact with both D1 and D2 receptors
  • Direct Pathway: Excited
  • Indirect Pathway: Inhibited
• Causes the body to perform a motor movement
• DA causes two opposite effects in the same brain area because of the receptor types found in networks of that brain area
• Cell's responses depend on the receptor type, not the NT type

Excitatory and Inhibitory NTs

Neuron Classification

• Many neurons are classified as either:
• Excitatory
• Inhibitory
• Characterized by the effect on the postsynaptic cell

Excitatory Neurons

• Neurons cause the postsynaptic cells to depolarize, increasing AP likelihood
• Typically forms synapses with the dendrites of the postsynaptic cell
• Most excitatory neurons release glutamate (Glu), the most common NT in the brain
• Classified as an excitatory NT
• Almost always excitatory
• Seldomly acts as inhibitory signal in some cells
• NTs are not intrinsically excitatory or inhibitory
• Glu typically binds to glutamatergic receptors
• Ex. AMPA Receptors, ionotropic Na+ receptor
• Glu binds, allowing Na+ to rush into the cell, depolarizing the membrane

Inhibitory Neurons

• Neurons cause the postsynaptic cells to hyperpolarize, decreasing AP likelihood
• Typically forms synapses with the cell body of the postsynaptic cell
• Most inhibitory neurons release gamma-aminobutyric acid (GABA), the second most common NT in the brain
• Classified as an inhibitory NT
• Almost always inhibitory, excitatory in some niche cases
• GABA typically binds to GABAergic receptors
• Ex. GABAa Receptors, ionotropic Cl- receptor
• GABA binds, allowing Cl- to rush into the cell, hyperpolarizing the membrane

Excitatory & Inhibitory Neurons

• Cells that produce Glu and GABA are produced across the whole brain, with no centralized location
• Both primarily interact with ionotropic receptors to either excite or inhibit other neurons

Neuromodulator NT

Neuromodulator NT

• A class of NTs that is important for a wide range of neural processes
• Neuromodulators have a more widespread influence on neural activity than the local signaling of Glu and GABA
• 4 Major NTs:
  • Acetylcholine (ACh)
  • Dopamine (DA)
  • Norepinephrine (NE)
  • Serotonin (5-HT)
• Each NT interacts with a wide class of receptors that influence many neural processes, and are not consistently excitatory or inhibitory
• These differ from Glu and Gaba based on how they modulate the brain and how they are produced

Modulation

• Modulate the activity of other neurons
• Primarily interact with GPCR, resulting in longer term cellular processes, compared to Glu and GABA

Production

• Less prevalent than Glu and GABA
• Each neuromodulator NT is produced in a centralized location where the cell body is located
• Axons extend far distances to communicate with certain structures

Production - DA Example

• DA is produced in the midbrain
• Axons extend to multiple targets
• Basal Ganglia
• Pituitary
• Cortex
• NTs are transported along axons to reach synaptic terminals and released in those locations

Investigation

• Neuromodulator NTs are being thoroughly investigated for their role in:
  • Cognition
  • Motor control
  • Neurological disorder
  • Clinical Depression
  • Substance Abuse Disorder
  • Generalized Anxiety
  • Etc.

Popular Culture

• Overgeneralizations about neuromodulator NTs are very common
• Be mindful of social media, podcasts, and videos making big claims that seem too straightforward
• Always check sources