Synapses and Chemical Transmission – Comprehensive Study Notes

2.1 The Concept of the Synapse

• Neurons communicate by transmitting chemicals at junctions called synapses
• The term “synapse” was coined by Charles Scott Sherrington in 1906
• Synapses describe the specialized gap between neurons where communication occurs
• Sherrington’s discovery was a major feat of scientific reasoning

Sherrington’s Approach to Synapses and Reflexes

• Investigated neuronal communication by studying reflexes (automatic muscular responses to stimuli) in reflex arcs
• Example: Leg flexion reflex
• Sensory neuron excites a second neuron
• Second neuron excites a motor neuron
• Motor neuron excites a muscle

The Relationship Among Sensory, Motor, and Intrinsic Neurons (illustrative wiring)

• Skin → Sensory neuron → brain → intrinsic neuron → motor neuron → muscle
• Emphasizes convergence of multiple neuron types in producing motor output

Three Important Points About Reflexes (Sherrington)

• Reflexes are slower than conduction along an axon
• Several weak stimuli at different times/locations can produce a stronger reflex than a single stimulus (temporal/spatial summation)
• As one set of muscles excites, another set relaxes (antagonistic control)

Difference in Speed of Conduction and the Synapse

• Speed along an axon ≈ 40 m/s
• Reflex arc conduction is slower and more variable (≈ 15 m/s or less) due to synaptic delay
• This slowing validated the idea of a synapse as the communication delay point
• Evidence supports synaptic delay as a limiting factor in reflex speed

Sherrington’s Evidence for Synaptic Delay (conceptual notes)

• Axonal conduction is fast; reflex arc conduction is slower and variable
• The difference is attributed to transmission between neurons at the synapse

Temporal Summation

• Repeated stimuli over a short period produce a stronger response
• Leads to the concept that the nervous system can sum inputs over time to reach threshold
• Mathematical intuition: multiple subthreshold EPSPs can summate temporally to reach threshold

EPSP: Excitatory Postsynaptic Potential

• Presynaptic neuron delivers the signal; postsynaptic neuron receives it
• EPSP: graded depolarization that decays over time and space
• The cumulative effect of EPSPs underlies temporal and spatial summation
• Net postsynaptic membrane potential change can be expressed as a sum of excitatory inputs

Spatial Summation (1 of 2)

• Several small stimuli at different locations can produce a reflex when a single stimulus does not
• Spatial summation: input from several locations has a cumulative effect to trigger a nerve impulse

Spatial Summation (2 of 2) and its importance

• Critical for brain functioning: neurons receive many incoming axons that can respond synchronously
• Temporal and spatial summation often occur together; the order and timing of axonal inputs influence the result

Recordings From a Postsynaptic Neuron During Synaptic Activation

• EPSP detected as membrane potential rises toward threshold
• Temporal summation of EPSPs can exceed threshold to trigger an action potential
• Simultaneous EPSPs can combine spatially to exceed threshold
• IPSPs can counteract EPSPs to prevent firing

Temporal and Spatial Summation (conceptual visuals)

• Temporal summation: several impulses from one neuron over time
• Spatial summation: impulses from several neurons at the same time
• Action potential travels along the axon when threshold is reached

The Effects of Summation (directionality of depolarization)

• Summation in a particular direction can produce greater depolarization
• Conversely, summation in another direction may produce less depolarization

Inhibitory Synapses

• Observed during reflexes where some legs extend while others flex or retract
• Suggests interneurons in the spinal cord send excitatory messages to flexors and inhibitory messages to extensors
• Demonstrates the existence of inhibitory pathways modulating reflexes

Antagonistic Muscles

• Flexors vs. extensors
• Activation of one group typically coincides with inhibition of the antagonistic group

IPSP: Inhibitory Postsynaptic Potential

• IPSP: temporary hyperpolarization of the membrane
• Occurs when synaptic input opens gates for Na+ to leave or Cl− to enter, hyperpolarizing the cell
• Serves as an active “brake” to suppress excitation

Sherrington’s Inference of Inhibitory Synapses

• Skin/nerve muscle illustration showing inhibitory vs excitatory synapses in reflexes
• Demonstrates how inhibitory synapses contribute to coordinated movement

EPSP, IPSP, and Action Potentials Relationship

• Synapses can produce on/off effects
• Different synapses have varying durations of effect
• The combined effect of multiple synapses at once can be more or less than additive

A Possible Wiring Diagram for Synapses

• Demonstrates convergence of multiple axons onto a single postsynaptic neuron
• Illustrates how summation and integration determine whether the neuron fires

Wiring Diagrams: “A or B” vs. “A and B” Responses

• A or B: threshold for neuron X is 1; either A or B alone can push X past threshold
• A and B: threshold for X is 2; both A and B are required to drive X past threshold

Spontaneous Firing Rate

• Neurons have a baseline rate of action potentials even without synaptic input
• EPSPs can increase firing above spontaneous rate; IPSPs can decrease firing below spontaneous rate

The Discovery of Chemical Transmission at Synapses

• Otto Loewi demonstrated chemical transmission as a mechanism across the synapse
• Stimulating one nerve released a chemical that inhibited heart rate; stimulating another nerve released a chemical that increased heart rate
• Conclusion: communication across synapses is chemical, not purely electrical

Chemical Events at the Synapse (overview)

• The neuron synthesizes neurotransmitters
• Action potentials travel down the axon
• Neurotransmitter molecules diffuse across the synaptic cleft, attach to receptors, and alter postsynaptic activity
• Neurotransmitters detach from receptors; may be recycled via reuptake or diffuse away
• Some postsynaptic cells may send reverse messages to slow further neurotransmitter release

Major Events in Transmission (illustrative sequence)

• Transporter proteins and vesicles store transmitter precursors
• Action potential causes Ca2+ influx, triggering exocytosis of neurotransmitter
• Neurotransmitter binds to receptors on the postsynaptic neuron
• Neurotransmitter is separated from receptors; broken down or taken back up
• Retrograde signaling can regulate presynaptic release
• Glia can be involved in modulation

Types of Neurotransmitters (categories)

• Amino acids: glutamate, GABA, glycine, aspartate, possibly others
• A modified amino acid: acetylcholine
• Monoamines: indoleamines (serotonin); catecholamines (dopamine, norepinephrine, epinephrine)
• Neuropeptides (chains of amino acids): endorphins, substance P, neuropeptide Y, many others
• Purines: ATP, adenosine, maybe others
• Gases: nitric oxide (NO), maybe others

Synthesis of Neurotransmitters

• Neurons synthesize transmitters from diet-derived substances
• Examples: acetylcholine synthesized from choline (diet/dairy), tryptophan as a precursor for serotonin
• Catecholamines: dopamine, norepinephrine, epinephrine derived from amino acids (tyrosine/dopa pathway)
• Pathways illustrate how basic nutrients lead to diverse signaling molecules

Pathways in the Synthesis of Transmitters (illustrative schematic)

• Acetyl-CoA + Choline → Acetylcholine
• Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine
• Tryptophan → 5-hydroxytryptophan → Serotonin (5-HT)
• These pathways show substrate origins and enzymatic steps

Storage of Transmitters

• Vesicles store neurotransmitters in the presynaptic terminal
• MAO (monoamine oxidase) breaks down excess monoamines
• Exocytosis: action potential triggers release into the synaptic cleft

Release and Diffusion of Transmitters

• Transmission across the 20–30 nm cleft takes less than 0.01 ms
• Most neurons release two or more different neurotransmitters
• Neurons may respond to more transmitter types than they release

Activating Receptors of the Postsynaptic Cell

• Receptor type determines the effect of the transmitter
• Transmitter-gated (ligand-gated) channels are controlled by a transmitter

Ionotropic Effects (direct, fast signaling)

• Transmitter binds receptor, opens ion channels immediately
• Effects are very quick (often < 1 ms) and brief
• Commonly involve glutamate (excitatory) and GABA (inhibitory)

The Acetylcholine Receptor (example of ionotropic receptor)

• Receptors have an outer membrane-facing portion and an inner portion surrounding the ion channel
• Structural illustration shows how acetylcholine binding opens the sodium channel

Metabotropic Effects and Second Messenger Systems (1 of 2)

• Metabotropic synapses involve slower, longer-lasting metabolic cascades
• Utilize several transmitters (e.g., dopamine, norepinephrine, serotonin; sometimes glutamate, GABA)

Metabotropic Effects and Second Messenger Systems (2 of 2)

• Binding bends the receptor; intracellular portion interacts with G proteins
• Initiates cascades affecting ion channels, enzyme activity, gene expression, and more
• Involves second messengers and longer-lasting cellular responses (e.g., taste, smell, pain processing)

Metabotropic Signaling Sequence (illustrative)

• Nonstimulated metabotropic receptor
• Neurotransmitter binds to receptor
• Receptor bends, releasing G protein
• G protein activates a second messenger (e.g., cyclic AMP), which alters cellular pathways or opens/closes ion channels or affects gene expression

G-Proteins and Second Messengers

• G-protein activation is coupled to GTP (guanosine triphosphate)
• Increases the concentration of second messengers
• Second messengers communicate within the cell to modulate activity
• Effects include opening/closing ion channels, activating proteins, or influencing gene expression

Neuropeptides and Neuromodulation

• Metabotropic effects often involve neuropeptides (neuromodulators)
• Release generally requires repeated stimulation
• Neuropeptides trigger other neurons to release the same neuropeptide
• Diffuse widely and affect many neurons via metabotropic receptors

Distinctive Features of Neuropeptides vs. Neurotransmitters

• Synthesis location: cell body for neuropeptides vs. presynaptic terminal for many small molecule transmitters
• Release: neuropeptides released from dendrites, soma, and sides of axon; neurotransmitters released mainly from axon terminal
• Spread and effect: neuropeptides diffuse to wide areas; neurotransmitter effects are more localized
• Duration: neuropeptide effects last minutes; fast transmitters last milliseconds to seconds
• Reuptake: neuropeptides are less likely to be rapidly recycled; - (differences summarized in the slide)

Drugs That Act by Binding to Receptors

• Hallucinogens (e.g., LSD) distort perception by stimulating serotonin type 2A receptors (5-HT2A)
• Nicotine stimulates acetylcholine receptors

Opiate Drugs and Endorphins

• Opiates bind to specific brain receptors
• Endorphins are endogenous peptides with morphine-like effects
• Opiate drugs bind to the same receptors as endorphins, producing similar effects

Inactivation and Reuptake of Neurotransmitters (1 of 2)

• Neurotransmitters do not stay in the synapse; they are inactivated or reuptaken
• Reuptake: presynaptic neuron reabsorbs transmitter molecules intact for reuse
• Transporter proteins facilitate reuptake

Inactivation and Reuptake of Neurotransmitters (2 of 2)

• Serotonin is taken back up into the presynaptic terminal
• Acetylcholine is broken down by acetylcholinesterase into acetate and choline
• Excess dopamine is converted into inactive chemicals by enzymes (e.g., COMT)

Stimulant Drugs and Dopamine

• Amphetamine and cocaine stimulate dopamine synapses by increasing dopamine release from the presynaptic terminal
• Methylphenidate (Ritalin) blocks dopamine reuptake more gradually and is often prescribed for ADD; concerns about later abuse are debated

Negative Feedback from the Postsynaptic Cell

• Autoreceptors: receptors that detect transmitter amount released and inhibit further synthesis and release
• Postsynaptic neurons can send retrograde signals to presynaptic terminals to inhibit further release

Cannabinoids

• Active compounds in marijuana bind to cannabinoid receptors on presynaptic neurons (anandamide/2-AG receptors)
• Cannabinoid binding reduces release of glutamate and GABA, thereby dampening both excitatory and inhibitory signaling across networks

Dopamine Synapses and Diet-Related Modulation (illustrative diagram notes)

• Tyrosine availability and conversion to DOPA can influence dopamine synthesis
• AMPT (a synthesis blocker) reduces dopamine production; DOPA can increase supply
• Various antidepressants affect dopamine pathways or receptor interactions
• Cannabinoids modulate dopamine pathways via receptor interactions, impacting release
• Cocaine blocks dopamine reuptake; methylphenidate and some antidepressants have similar effects but with different potency/duration

Electrical Synapses

• A small subset of synapses are electrical rather than chemical
• Gap junctions provide direct cytoplasmic continuity between adjacent neurons
• Depolarization in one neuron spreads to the other, making them functionally act as a single unit
• Faster than chemical transmission; rapid synchronization

A Gap Junction for an Electrical Synapse

• Gap junction channels connect presynaptic and postsynaptic membranes; ions pass through to synchronize activity

Hormones and the Endocrine System (overview)

• Hormones are chemicals secreted by glands into the bloodstream to alter activity in distant organs
• Endocrine glands produce hormones that regulate various bodily functions
• Important for triggering long-lasting changes across multiple body systems

Location of Major Endocrine Glands (high-level map)

• Hypothalamus, Pineal gland, Pituitary gland, Parathyroid glands, Thyroid, Thymus, Liver, Adrenal glands, Kidneys, Pancreas, Ovaries, Placenta, Testes

Select Hormones and Functions (partial list)

• Hypothalamus: releasing and inhibiting hormones controlling the pituitary
• Anterior pituitary: TSH, LH, FSH, ACTH, prolactin, growth hormone; stimulates thyroid, gonads, adrenal cortex activity, etc.
• Posterior pituitary: oxytocin, vasopressin (antidiuretic hormone)
• Pineal: melatonin (sleepiness, puberty role)
• Adrenal cortex: aldosterone, cortisol (salt balance, metabolism, stress response)
• Adrenal medulla: epinephrine, norepinephrine (sympathetic-like responses)
• Pancreas: insulin, glucagon (glucose regulation)
• Gonads: estrogens, progesterone, testosterone (sexual development and reproduction)
• Kidney: renin (blood pressure regulation, fluid balance)
• Fat cells: leptin (appetite regulation)

The Pituitary Gland and the Hypothalamus

• Anterior pituitary: glandular tissue; hypothalamic releasing/inhibiting hormones regulate its secretion
• Posterior pituitary: neural tissue; hypothalamus produces oxytocin and vasopressin which are released in response to neural signals
• Interaction forms a core part of the hypothalamic-pituitary axis controlling endocrine outputs

Location and Organization in the Brain

• Hypothalamus and pituitary located in the brain with anatomical connections such as the pituitary stalk
• The hypothalamus sits near the third ventricle and influences pituitary activity via neural and vascular routes

Pituitary Hormones and Pathways (summary)

• Anterior pituitary releases several trophic hormones that regulate peripheral glands
• Posterior pituitary releases oxytocin and vasopressin directly in response to hypothalamic signals
• Hormonal cascades often involve feedback loops to the hypothalamus and pituitary

Negative Feedback in Hormonal Control (conceptual)

• The hypothalamus maintains relatively constant circulating hormone levels via negative feedback loops
• Example: Thyroid-Stimulating Hormone (TSH) release and thyroid hormones (thyroxine, T4; triiodothyronine, T3) feedback to hypothalamus and pituitary to regulate further release

Key Connections to Foundational Principles and Real-World Relevance

• The synapse is a fundamental mechanism enabling complex processing beyond direct neural conduction
• Temporal vs. spatial summation provide a basis for how neurons integrate signals from many sources to decide on firing
• Chemical transmission allows diverse modulation via receptor types, second messengers, and neuromodulators, underpinning learning, memory, sensation, and behavior
• Inhibitory transmission and autoreceptors demonstrate how neural circuits are regulated for stable function
• Drugs and hormones illustrate how biology can be modulated to treat disease or alter behavior, highlighting therapeutic targets and ethical considerations
• Electrical synapses show that not all communication relies on chemical signaling; they enable rapid synchronization in networks
• The hypothalamus–pituitary–endocrine axis shows how the brain governs body-wide physiology through hormones and feedback loops, linking nervous and endocrine systems

Notation and Formulas to Remember

• Postsynaptic integration concept (illustrative):
• Total postsynaptic potential: $V_{ ext{total}} = \big( extstyle\big( ext{sum of EPSPs}\big) - \big( extstyle\big( ext{sum of IPSPs}\big)\big) \big)$
• Threshold concept (for an action potential):
• If $V<em>{ ext{total}} \ge V</em>{ ext{threshold}}$, then an action potential is generated
• Temporal summation (simple model):
• Each EPSP decays with time constant $\tau$: $V<em>i(t) = A</em>i \exp(-t/\tau)$ for t after arrival
• $V<em>{ ext{total}}(t) = \sum</em>i V_i(t)$ until threshold is reached
• Neurotransmitter life-cycle (conceptual loops): synthesis → storage in vesicles → release into cleft → receptor binding → reuptake/enzymatic breakdown → recycling or diffusion

Quick Reference: Common Terms

• EPSP: excitatory, depolarizing input
• IPSP: inhibitory, hyperpolarizing input
• Autoreceptor: presynaptic receptor that inhibits transmitter synthesis/release
• Neuromodulator: neuron signaling that modulates activity across networks (often neuropeptides)
• Metabotropic receptor: receptor that triggers slower, longer-lasting intracellular cascades via second messengers
• Ionotropic receptor: receptor that directly controls an ion channel, fast signaling
• Gap junction: connection facilitating electrical synapses
• Exocytosis: release of neurotransmitters from vesicles into the synaptic cleft
• Reuptake: presynaptic reabsorption of neurotransmitter for reuse
• MAO/COMT: enzymes that inactivate monoamines
• Autoreceptor vs. heteroreceptor: autoreceptors regulate transmitter release from the same neuron; heteroreceptors regulate release from other neurons