Neural Transmission and Postsynaptic Potentials (Chapters 1-5)

Postsynaptic Potentials and Neurotransmitter-Dependent Ion Channels

• Overview: Neurotransmitters in the synapse bind to postsynaptic receptors, opening ion channels directly (ionotropic receptors) or indirectly via G-protein coupled cascades (metabotropic receptors).
• After channels open, the same basic membrane-potential dynamics seen in axons occur: ions flow, and the local membrane potential moves away from the resting potential.
• Key concept: opening neurotransmitter-dependent ion channels produces postsynaptic potentials (PSPs).
• Four main types of neurotransmitter-dependent ion channels: $Na^+,$ $K^+,$ $Cl^-,$ and $Ca^{2+}$ channels.

Neurotransmitter-Dependent Ion Channels and PSP Outcomes

Sodium (Na+) channels

• Binding of neurotransmitter to the Na+ channel binding site opens the channel.
• Influx of sodium ions causes depolarization: positive ions entering make the inside less negative.
• This depolarization is called an Excitatory Postsynaptic Potential (EPSP).
• Mechanism detail: depolarization = membrane potential becomes less negative due to positive charge entry.
• Connection to action potential: same basic idea as the Na+ influx that initiates an action potential in the axon, but here it occurs at the postsynaptic membrane.

Potassium (K+) channels

• Neurotransmitter binds to the potassium channel, opening it.
• Potassium leaves the cell, causing hyperpolarization (the inside becomes more negative).
• Hyperpolarization is an Inhibitory Postsynaptic Potential (IPSP).
• Rationale: loss of positive charges (or the inside becoming more negative) drives the membrane further from the threshold.

Chloride (Cl^-) channels

• Neurotransmitter binding opens Cl^- channels.
• Chloride ions enter the cell (negative ions move inward).
• Result is hyperpolarization, i.e., IPSP, since the inside becomes more negative relative to the outside.
• Similar outcome to K+ channels for the postsynaptic potential (inhibitory).

Calcium (Ca^{2+}) channels

• Neurotransmitter binding opens Ca^{2+} channels.
• Calcium ions rush into the postsynaptic neuron, causing depolarization (positive charges entering).
• This is an EPSP, i.e., excitatory.
• Calcium has additional roles beyond PSPs: it can trigger enzyme-based cascades that produce longer-term intracellular changes.
• Calcium involvement in learning-related biochemical and structural changes will be discussed in later weeks.

Terminology and Core Concepts: AP vs PSP

Action Potential (AP)

• AP occurs down the presynaptic axon, not in the postsynaptic neuron.
• Resting potential: $V_{rest} \,\approx\, -70\ \text{mV}$, with outside positive and inside negative.
• The AP is the full pattern of depolarization followed by hyperpolarization that travels along the axon.
• APs are all-or-nothing: once triggered, they have the same shape and magnitude.

Postsynaptic Potential (PSP)

• PSPs occur in the postsynaptic neuron after neurotransmitter binding.
• Resting potential is still $V_{rest} \,\approx\, -70\ \text{mV}$ in the postsynaptic cell.
• PSPs can be either depolarizing (EPSP) or hyperpolarizing (IPSP).
• Unlike APs, PSPs are graded: their size can be small or large depending on neurotransmitter release, receptor activation, and ion conductance.

Key distinctions

• APs are depolarization followed by hyperpolarization; PSPs are either depolarization or hyperpolarization (not both in sequence).
• EPSPs = depolarizing PSPs; IPSPs = hyperpolarizing PSPs.

How PSPs End: Termination and Regulation

• Do PSPs continue forever? No. The synapse must stop signaling to allow changes in firing rate to be detected.

Reuptake (major termination mechanism for many neurotransmitters)

• Neurotransmitter molecules are returned to the presynaptic neuron via reuptake transporters.
• Some neurotransmitter molecules diffuse away; the rest are taken back into the presynaptic terminal for reuse.
• Reuptake relevance: selective serotonin reuptake inhibitors (SSRIs) block this process, increasing serotonin presence in the synapse to enhance signaling.
  • Examples: Prozac, Zoloft, etc., which prolong serotonin action in the synapse.

Enzymatic deactivation (alternative termination mechanism)

• Some neurotransmitters are terminated by enzymatic breakdown in the synaptic cleft.
• Acetylcholine (ACh) is broken down by acetylcholinesterase in the postsynaptic membrane, quickly deactivating ACh.
• Result: PSPs produced by ACh are very short-lived.
• Clinical example: myasthenia gravis is an autoimmune disorder where postsynaptic ACh receptors are destroyed, making muscle activation harder.
  • One treatment strategy is to administer drugs that inhibit acetylcholine degradation (AChE inhibitors), which keeps ACh in the synapse longer and increases the chance of binding to the remaining receptors, helping to restore muscle signaling.
• Similar enzymatic deactivation applies to other peptide neurotransmitters (context not detailed here).

Autoreceptors and Presynaptic Regulation

Autoreceptors (self-receptors on the presynaptic neuron)

• Located on the presynaptic terminal; respond to the neurotransmitter released by that neuron.
• Most autoreceptors are metabotropic (not ion channels) and couple to G proteins/second messengers.
• Function: regulate internal processes to adjust neurotransmitter synthesis and release (positive or negative feedback), thereby modulating synaptic strength.
• They can increase or decrease how much neurotransmitter is produced or released in response to an action potential.

Axo-axonic synapses

• A subset of synapses where the terminal button of one neuron forms a synapse onto the terminal button of another neuron.
• This presynaptic neuron can regulate neurotransmitter release from the second neuron by modulating calcium channel activity:
  • Facilitation: keeps calcium channels open, increasing neurotransmitter release.
  • Inhibition: blocks calcium channels, reducing release.
• Functional implications: can fine-tune synaptic output; mechanism implicated in various drug effects (e.g., marijuana) via presynaptic modulation.

Postsynaptic Receptor Plasticity and Glial Modulation

Receptor density and sensitivity

• The post-synaptic cell can adjust the number of receptors (increasing or decreasing) and alter receptor sensitivity.
• Such plasticity affects how easily the postsynaptic neuron reaches threshold and thus how it responds to neurotransmitter release.

Glial modulation

• Glial cells can influence neurotransmitter release indirectly, for example via glutamate signaling in the synaptic environment.
• This glial involvement can modulate the efficiency and dynamics of neurotransmitter release from the presynaptic terminal.

Relevance and Connections

• Pharmacology connections:
  • SSRIs increase synaptic serotonin by blocking reuptake, illustrating how manipulating termination alters PSPs and downstream signaling.
  • AChE inhibitors for myasthenia gravis illustrate therapeutic strategies that prolong neurotransmitter presence, enhancing signaling at muscle synapses.
• Learning and plasticity:
  • Calcium-dependent signaling cascades in postsynaptic neurons can trigger biochemical and structural changes linked to learning and memory.
• Behavioral pharmacology:
  • Axo-axonic modulation explains how certain drugs (e.g., cannabinoids) alter neurotransmitter release and brain signaling patterns.

Quick Reference: Key Terms and Equations

• Resting potential: $V_{rest} \,\approx\, -70\ \text{mV}$
• Depolarization: membrane potential becomes less negative (e.g., due to $Na^+,$ $Ca^{2+}$ influx).
• Hyperpolarization: membrane potential becomes more negative (e.g., due to $K^+$ efflux or $Cl^-$ influx).
• EPSP: excitatory postsynaptic potential (depolarizing PSP).
• IPSP: inhibitory postsynaptic potential (hyperpolarizing PSP).
• Ion channel types: $Na^+,$ $K^+,$ $Cl^-,$ $Ca^{2+}$ channels.
• Auto receptors: presynaptic metabotropic receptors that regulate neurotransmitter synthesis/release via G proteins.
• Axo-axonic synapse: presynaptic regulation of another neuron’s neurotransmitter release (facilitation or inhibition).
• Enzymatic deactivation: breakdown of neurotransmitter by enzymes (e.g., acetylcholinesterase for acetylcholine).
• Reuptake: transporter-mediated removal of neurotransmitter from synapse back into presynaptic neuron; target of SSRIs.
• Learning-related signaling: calcium-dependent cascades can drive synaptic changes underlying learning.

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