PS231: Neuropharmacology I

Clostridium bacteria

produce several botulinum and tetanus toxins that cleave various SNARE proteins to inhibit vesicle fusion (e.g. BOTOX)

Lambert-Eaton Myasthenic Syndrome

An autoimmune disorder affecting presynaptic calcium channels at the NMJ, resulting in reduced NT release and muscle weakness

Black Widow Spider Toxin

stimulates NT release at NMJs, even in the absence of calcium

Congenital Myasthenic Syndromes

interfere with vesicle recycling, reducing the number of vesicles in motor nerve terminals

Studying receptors

Each receptor binds a single neurotransmitter type, but a given neurotransmitter type can often bind to multiple receptor types

Postsynaptic response

determined by the type of receptors that bind to released neurotransmitters

Neuropharmacological analysis

responsible for most of what we know about ligand/receptor interactions (ligand = any molecule that binds to a receptor)

Neuropharmacology

concerned with the discovery and study of compounds that affect the nervous system and behavior

• These can be naturally occurring chemicals (e.g. neurotransmitters, neurohormones, toxins, etc.) or synthesized (e.g. therapeutic medications or some psychoactive drugs)

Ionotropic

transmitter gated ion channels, let ions in directly to either excite (depolarize) or inhibit (hyperpolarize) the neuron

Metabotropic

indirectly let ions in, slower since there’s several steps involved, but usually result in a stronger signal (e.g. larger depolarization) due to signal amplification; more ion channels activated 

The same neurotransmitter can sometimes

activate ionotropic and metabotropic receptors, neurotransmitters are versatile—a single neurotransmitter might interact with multiple different receptor subtypes

Fast transmission: ionotropic ligand-gated channels

• Physical (“gating”) properties of the receptor channel determine which ions are allowed to flow (sometimes several), and the effect is rapid (~1 ms)

• Multiple receptors are opened by the synaptic release of neurotransmitter

• The effect of a neurotransmitter on a neuron depends on the receptors expressed, membrane voltage, and ion concentrations

• The “ligand” is the neurotransmitter (green dots) and red arrows represent the flow of ions in and out of the receptor’s ion channel pore, once opened

Excitatory current flow: ionotropic receptors

Inhibitory current flow: ionotropic receptors

PSP integration in space

PSP integration in time

Depolarization in the dendrites

decreases as a function of distance (passive conductance)

Synaptic Integration & Summation of PSPs

• Neurons summate the EPSPs and IPSPs they receive

• It is the summed PSP that determines whether a neuron fires

• Spatial and temporal factors affect the magnitude of the PSP

Summation

allows the post-synaptic neuron to integrate the electrical information provided by all inhibitory and all excitatory synapses acting on it at any given moment

Compare and contrast the two major types of post-synaptic receptors: ionotroic and metabotropic receptors. How do they work and what are the advantages and drawbacks of each receptor type with regard to speed and signal strength?

Ionotropic Receptors

• Type: Ligand-gated ion channels

• Speed: Fast (milliseconds)

• Signal: Direct ion flow → brief, localized

• Advantage: Rapid response

• Drawback: Limited modulation

Metabotropic Receptors

• Type: G-protein-coupled receptors

• Speed: Slow (seconds to minutes)

• Signal: Intracellular cascade → amplified, prolonged

• Advantage: Versatile effects

• Drawback: Slower, energy-intensive

What is an EPSP? What is an IPSP? Give an example of a neurotransmitter that causes EPSPs in the postsynaptic neuron and an example of a neurotransmitter that causes IPSPs in the postsynaptic neuron. Influx of which type of ion (cation or anion) are usually responsible for each of these two types of potentials?

EPSP (Excitatory Post-Synaptic Potential)

• Effect: Depolarizes membrane → ↑ chance of AP

• Neurotransmitter: Glutamate

• Ion: Cation influx (Na⁺, Ca²⁺)

IPSP (Inhibitory Post-Synaptic Potential)

• Effect: Hyperpolarizes membrane → ↓ chance of AP

• Neurotransmitter: GABA

• Ion: Anion influx (Cl⁻) or K⁺ efflux

Describe the difference between spatial summation and temporal summation in your own words.

Spatial Summation

• Multiple synapses fire simultaneously

• Signals from different locations add up

Temporal Summation

• One synapse fires repeatedly

• Signals build up over time

How do spatial and temporal summation relate to the concept of synaptic integration in the dendrites?

• Both types of summation contribute to synaptic integration.

• The neuron acts like a calculator, adding up all EPSPs and IPSPs.

• If the net result reaches the threshold, the neuron fires an action potential.

What is synaptic integration?

• Definition: The process by which a neuron adds up all incoming excitatory (EPSPs) and inhibitory (IPSPs) signals from its synapses.

• Location: Occurs mainly in the dendrites and soma of the neuron.

• Purpose: To determine whether the membrane potential reaches the threshold needed to trigger an action potential at the axon hillock.

How does a neuron “decide” whether or not to fire an action potential?

• Step 1: Neuron receives multiple inputs (EPSPs and IPSPs) from other neurons.

• Step 2: These inputs are summed through:

  • Spatial summation: Signals from different locations at the same time.

  • Temporal summation: Signals from the same location in rapid succession.

• Step 3: If the net effect of all inputs depolarizes the membrane to the threshold level (usually ~–55 mV), the neuron fires an action potential.

• Step 4: If the threshold is not reached, no action potential occurs.