📗 -> 04/15/25: NPB173-L5

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🎤 Vocab

❗ Unit and Larger Context

Overview

Cellular neuroscience: neurons as building blocks of neural systems
Action potential biophysics - “if a neuroscientist could understand something reeally well, it should be this”
Synaptic transmission
Mechanisms of seizures and causes of epilepsy
From understanding to treatment: translational neuroscience in epilepsy

Lecture 5 learning objectives

Action potential biophysics.
Synaptic transmission.
Types of epilepsy and seizures.
EEG.
Interictal spikes and potential causes.
Epileptogenesis
Possible mechanisms of overexcitability.
Avenues for translational neuroscience in epilepsy

✒️ -> Scratch Notes

Cellular Neuroscience - The study of individual neurons and their properties

Classifying neurons into distinct types
Use of cell cultures to study plasticity
etc.
Useful lens for understanding epilepsy

Ion - Molecule with an electrical charge. The membrane is not permeable to central ions
Ion Pumps - Use energy to maintain concentration gradients of Na and K. High Na outside, high K inside
Ion Channels - Selectively permeable channels that allow some specific ions to diffuse through it (down its gradient)
Resting Membrane Potential - Static electrical potential across its membrane in the absence of synaptic input

Set by the net flow / equilibrium of passive ion difussion

Mechanism of Action Potential

Resting state - Gates on Na+ and K+ channels are closed, membrane is at resting potential
Depolarization - A stimulus pens the activation gates on some Na+ channels, causing depolarization
Rising phase of action potential - This is the big jump. Depolarization opens the activation gates on most Na+ channels, while K+ channels remain closed. Na+ influx makes the inside of the membrane positive with respect to the outside.
Falling phase of the action potential - Inactivation gates on most Na+ channels close, block Na+ influx. The activation gates on most K+ channels open, permitting K+ efflux which makes the inside negative again
Undershoot - Both gates close, but the activation gates on some K+ channels remain open. As these gates close on most K+ channels and the inactivation gates open on Na+ channels, the membrane returns to its resting state

Propagation of action potentials

Action potentials are usually initiated at the neuron’s cell body (soma)
Depolarization spreads along the axon. In myelinated parts of the axon, the spread is “passive” with electrical orces moving positive ions inside the axon
At un-myelinated parts of the axon (could be Nodes of Ranvier, or just no myelin at all) the depolarization triggers an action potential at that part of the membrane
This continues down the axon

The refractory period precludes reversal of direction during action potential propagation ?

Neuron Communication

Neurons are connected in a variety of ways
In cortex, reverberating connections are most common

Synapses:

Communication between neurons mediated by synapses
Can be electrical or chemical
- Electrical - gap junctions allowing ions to pass directly
- Chemical - Transmission via neurotransmitters
Generally connect to dendrites or cell bodies

Excitatory and Inhibitory Synapses

The presynaptic neurotransmitter and the postsynaptic receptors determine the effects of neurotransmitter release
- Not one size fit all, sometimes depolarization can be inhibitory
By and large, a neuron uses the same neurotransmitter at all of its presynaptic terminals, but has multiple receptors (postsynaptic).
Excitatory synapses - Increase the probability of postsynaptic action potentials upon neurotransmitter release
Inhibitory synapses - Decrease the probability of postsynaptic action potentials upon neurotransmitter release
The most common excitatory neurotransmitter is glutamate. Most common inhibitory neurotransmitters are GABA and glycine

Measurement

Intracellular recordings allow measurement of a neuron’s membrane potential

Action potential and sub threshold fluctuations can be directly measured with intracellular recordings
Extracellular recordings allow detection of action potentials, but not subthreshold changes in membrane potential
Signatures depend on electrode placement and activity from other nearby neurons

Non-invasive measurement of brain electrical activity

EEG (electroencephalography)

Result of brain activity filtered through large amounts of tissue
EEG patterns are related to state of the brain, with major differences depending on level of wakefulness/alertness
EEG signals result from synchronous activity across many neurons
When it occurs at rhythmic intervals, it is considered oscillatory activity

Epilepsy

Epileptic seizures often involve “hypersynchronous” neural activity

Seizures are the signs and symptoms related to bouts of abnormally excessive and/or synchronous neural activity in the brain

Can involve motor responses or none at al
Epilepsy is the diagnosis given to the condition of exhibiting seizures
Convulsive seizures involve uncontrolled shaking of the body

Impacts of epilepsy

Epilepsy affects 50 million people worldwide.
In USA, incidence (number of new cases per year) is 40-70 per 100,000 people.
More than double in developing countries.
In USA, prevalence (number of people with a disorder at a given time) is 5-10 per 1000. The lifetime prevalence (number of people with a disorder at some point in their life) is 3%.
Sudden unexpected death in epilepsy (SUDEP) is estimated to occur in 1 out of every 10,000 new diagnoses of epilepsy.
Estimated to cost U.S. economy around $15.5 billion per year (about 1% of costs of all disorders of brain function).

Classification of seizures and epilepsy

Clasification:

Seizures - Classified by their signs and symptoms
Epilepsies - Classified from the perspective of their inferred cause

Seizures are often distinguished as focal (occurring one area of the brain) versus generalized (occuring in multiple brain areas, usually in both hemispheres)
Seizures are also distinguished based on behavioral characteristics

Tonic Seizures - Involve rigidity from persistent extensor muscles
Clonic Seizures - Involve rhythmic muscle contractions and relaxations
Tonic-clonic Seizures / Grand mal seizures - Involve both
Atonic Seizures - Involve loss of muscle tone )often causing a fall or loss of posture
Absence Seizures / Petit mal seizures - Involve staring and unresponsiveness

Ictal Period - When it occurs
Interictal Period - Between seizures. Majority of the time for those with epilepsy. May still exhibit epilepsy signs
- Interictal spikes - Shown in red arrows, are one sign of epilepsy
Preictal period - Just before a seizure is triggered

Interictal spikes are associated with a paroxysmal depolarization shift (PDS) for many individual neurons.
- A sudden large depolarization of a neuron with multiple action potentials produces
Two competing hypotheses for PDS to consider:
1. Epileptic neurons - Encompasses the idea that neuronal properties are overexcitable (IE altered NA channels, or )
2. Giant synaptic potentials - Encompasses the idea that synaptic transmission can lead to overexcitability (IE altered glutamate receptors)

Over-excitability

Epileptic Neuron Hypothesis - Encompasses the idea that neuronal properties are overexcitable (IE altered NA channels)

Giant synaptic potentials - Encompasses the idea that synaptic transmission can lead to overexcitability (IE altered glutamate receptors)

Changes in neural circuits could also lead to overexcitability, excitatory/inhibitory balance as a result of altered number of GABA input.

Developing Epilepsy

Most forms of epilepsy are not present at birth and instead emerge during the lifetime

Emergence is called epileptogenesis (the process through which a non-epileptic brain become epileptic)
Seizures often increase in severity during epileptogenesis
Kindling model - Epilepsy is induced and worsened through repeated brain stimulation. Theorized that seizures have a causal role in worsening

Translational Neuroscience

Antiseizure drugs (ASDs) are the first line of treatment for epilepsy

Surgery is often needed for ASD resistant epilepsy. EEG and invasive neural recordings can be used to localize seizure focus for potential removal

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NPB173-L5