Synaptic Transmission: Chemical Synapse, Neurotransmitters & Action

Synaptic integration is the process by which neurons combine multiple inputs. The postsynaptic cell sums excitatory and inhibitory postsynaptic potentials. Excitatory postsynaptic potentials (EPSPs) depolarize the postsynaptic membrane, bringing it closer to threshold. Inhibitory postsynaptic potentials (IPSPs) hyperpolarize the membrane, moving it away from threshold. If the total depolarization reaches threshold (-55 mV), an action potential is generated. Acetylcholine effects are transient because acetylcholinesterase enzyme breaks down acetylcholine in the synaptic cleft, closing receptor channels and returning the membrane to resting state.

Postsynaptic potentials are graded potentials generated by receptor activation that determine whether a neuron fires. Excitatory postsynaptic potentials (EPSPs) occur when neurotransmitters open sodium or calcium channels, depolarizing the membrane and moving it toward the threshold for action potential firing. Inhibitory postsynaptic potentials (IPSPs) occur when neurotransmitters open potassium or chloride channels, hyperpolarizing the membrane and moving it away from threshold. Each neuron receives thousands of synaptic inputs generating both EPSPs and IPSPs that propagate as graded potentials to the trigger zone. These potentials summate spatially (multiple inputs) and temporally (multiple inputs arriving in sequence). A single EPSP rarely reaches threshold, but summation of multiple EPSPs may push the membrane potential to threshold, triggering an action potential. This integration process enables complex neural computations from simple synaptic interactions.

Neurons integrate multiple excitatory (EPSPs) and inhibitory (IPSPs) postsynaptic potentials through spatial and temporal summation; EPSPs cause membrane depolarization while IPSPs cause hyperpolarization, and the balance between these opposing signals determines whether the neuron reaches the threshold to generate an action potential in the axon initial segment, where voltage-gated sodium channels are densely expressed.

Neurons integrate incoming signals through algebraic summation at the axon hillock, where excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) combine; if the total EPSP reaches or exceeds the threshold, an action potential is generated, otherwise no signal passes. This integration process is demonstrated through experiments showing that inhibitory neurotransmitters like GABA cause hyperpolarization (IPSP), while excitatory neurotransmitters like acetylcholine cause depolarization (EPSP), and that drugs like benzodiazepines enhance GABA's binding to post-synaptic receptors, increasing inhibitory effects.

Neuronal integration is the process by which neurons process information from multiple synapses. Each neuron has tens of thousands of synapses that can be excitatory or inhibitory. The sum of postsynaptic potentials integrates excitatory and inhibitory electrical information. Two summation processes exist: spatial summation combines simultaneous potentials at different dendritic locations, while temporal summation combines rapid successive potentials at the same location within 15 milliseconds. If the integrated threshold is reached, an action potential is generated; otherwise, the neuron remains at rest.

Learning and memory depend on synaptic plasticity—the ability of neural connections to change. Long-term potentiation (LTP) demonstrates this: repeated high-frequency stimulation strengthens synaptic connections through calcium-dependent mechanisms that increase synapse size and efficiency. The discovery that specific glutamate receptor blockers prevent LTP confirmed glutamate's essential role in synaptic strengthening. This cellular mechanism explains how experiences physically alter neural circuits, encoding information in the structure of neural networks rather than merely as chemical signals.

Synaptic plasticity—the ability of synapses to strengthen or weaken—is the cellular basis for learning and memory, mediated by NMDA receptors that detect coincident pre- and postsynaptic activity; long-term potentiation (LTP) involves calcium influx through NMDA receptors activating CAMKII and other kinases to increase AMPA receptor number and conductance, while long-term depression (LTD) involves similar calcium signals but produces synaptic weakening, with different phases of plasticity (induction, expression, maintenance) requiring distinct molecular mechanisms.

Long-term potentiation (LTP) and long-term depression (LTD) represent enduring forms of synaptic plasticity essential for learning and memory. LTP occurs at glutamatergic synapses through a cascade: presynaptic glutamate release activates postsynaptic AMPA receptors, causing depolarization that removes magnesium block from NMDA receptors. Calcium influx through NMDA channels triggers protein activation that either phosphorylates existing AMPA receptors or inserts new ones into the membrane, increasing synaptic strength for hours or days. Conversely, LTD occurs at low frequencies (1 Hz) where insufficient calcium activates phosphatases instead of kinases, causing AMPA receptor dephosphorylation and removal from the membrane. These opposing mechanisms allow the nervous system to strengthen useful connections while weakening unused ones, forming the cellular basis of learning and memory storage.

Long-term potentiation (LTP) is the cellular mechanism underlying learning and memory, where repeated firing of a presynaptic neuron leads to increased neurotransmitter release (glutamate), which binds to AMPA and NMDA receptors on the postsynaptic neuron; the increased sodium influx through AMPA receptors causes sufficient depolarization to remove magnesium block from NMDA receptors, allowing calcium entry that activates calcium-calmodulin kinase pathways, resulting in phosphorylation and insertion of more AMPA receptors, along with retrograde signaling via nitric oxide and transcription factor activation that increases synaptic connections and maintains elevated EPSP and action potential responses.

Various substances affect synaptic transmission: caffeine, theobromine, and theophylline increase transmission by blocking adenosine receptors; strychnine blocks inhibitory glycine receptors; anesthetics and sedatives decrease transmission by enhancing inhibitory effects. Botulinum toxin blocks acetylcholine release at the neuromuscular junction, causing flaccid paralysis used therapeutically for wrinkles and overactive bladder. Tetanus toxin blocks inhibitory neurotransmitter release in the spinal cord, causing uncontrolled muscle spasms. These examples demonstrate how synaptic mechanisms can be pharmacologically modulated for therapeutic purposes.

This video explains how drugs and chemical substances interfere with normal synaptic transmission between neurons. Synaptic transmission involves five steps: electrical signal arrival, neurotransmitter release, receptor binding, signal cascade initiation, and neurotransmitter recycling. Drugs can activate or inhibit this process at different stages. For example, nicotine, morphine, and heroin activate electrical signals; amphétamines increase neurotransmitter release; cocaine and ecstasy inhibit neurotransmitter recapture; nicotine also reduces neurotransmitter recycling. These substances particularly affect neurons involved in pleasure processing, producing enjoyable sensations but also creating dependence and potentially toxicomania, as the brain becomes dependent on these artificial signals.

Drugs affect synaptic transmission by acting as agonists or antagonists on neurotransmitter receptors, altering the production, storage, release, or degradation of neurotransmitters such as serotonin, dopamine, and GABA; depressants like alcohol and opioids reduce CNS activity, stimulants like caffeine increase alertness through adenosine receptor blockade, and hallucinogens like LSD alter perception by acting as partial agonists on serotonin receptors.

Neurons communicate at synapses where presynaptic terminals release neurotransmitters stored in vesicles. Neurotransmitters can be excitatory (promoting action potentials) or inhibitory (preventing them). Despite ~100 billion neurons, only ~few hundred neurotransmitters exist due to brain compartmentalization—different neural networks in separate brain regions use the same neurotransmitters for different functions. Major neurotransmitters include dopamine (reward, motor control), epinephrine/norepinephrine (fight-or-flight), serotonin (sleep, appetite, mood), acetylcholine (muscle contraction), GABA (inhibitory), and glutamate (excitatory). To qualify as a neurotransmitter, substances must meet three criteria: synthesized and stored in presynaptic terminals, released by action potentials, and produce measurable effects on postsynaptic neurons. After signaling, neurotransmitters are removed via reuptake or degradation. Treatment challenges arise from brain compartmentalization—treating one region affects others, as seen in Parkinson's disease where global dopamine increase risks inducing schizophrenia-like symptoms.

Drugs affect synaptic transmission through multiple mechanisms: (1) Inhibiting neurotransmitter synthesis prevents production; (2) Blocking release prevents vesicle exocytosis; (3) Preventing reuptake prolongs neurotransmitter action; (4) Blocking receptors prevents neurotransmitter binding. These mechanisms can enhance or diminish neuronal signaling. Understanding these mechanisms is crucial for developing therapeutic drugs and understanding drug abuse effects on brain function.