BIO408 - TT1

Stephen Kuffler

Formed the first department of Neurobio in Harvard in 1966

Hippocrates

Idea of the brain as center for emotions and intelligence

Aristotle

Said the heart as centre of thought and emotions and the brain acts like a radiator

Galen

Brain is similar to the heart and so, its ventricles are like chambers of the heart 

Vesalius

Still talked about the humoural theory - focus on ventricles

Descartes

Focus on ventricles - idea that they connect to control movement

18-19th Century Neurosci

Change from humoural theory to modern views due to increase in scientific process and methods

18th-19th Century Neurosci lead to the findings of

• nerves as electrical wires

• Different brain

• Neutron doctrine - Cajal

Ventral Areas control

Motor functions

Dorsal Areas control

Sensory functions

4 Basic types of signal potentials

Resting membrane potentials, receptor potentials, Synaptic potentials, action potentials

Resting Membrane potential

baseline for all cells - don’t carry info and sre ‘static’

Receptor potentials

small amplitudes that are sensory inputs turned into electrical inputs → touch to signal

Synaptic Potentials

Synapse at neurons where its information from one neuron/area to another

Action potentials

largest amplitudes and are fixed in waveform → quickest form of signalling

Neural signals occur when

ions create electrical charges that move by ion [C] gradient

Ion levels in a cell

• K = 100mM in side, 5mM out

• Na = 15mM inside, 150mM out

• Cl = 13 mM inside, 150mM out

• Ca = 0.0002mM inside, 2mM out

Active transporters

• ATPase pup

• Ion exchanger

Need energy from ATP or [C] gradients of other ions 

ATPase Pumps

Na/K pump = low Na in, high K in

Ca²⁺ pump = low Ca in

How does the Na/K ATPase pump work?

1. conformation change that allows Na binding and ATP binds

2. pump becomes phosphorylated → P only and pump closed

3. conformational change to release Na out and K binds from outside

4. Pump phosphorylated and loses P

5. ATP binds to let K inside and Na binds again 

6. restart

How many Na/K get bound/let out or in?

3 Na out and 2 K in

How do Ion exchangers work?

Use the energy of the Na/K [C] gradients made from ATPase pumps

What are the two main categories of ion exhangers?

Antiporters and co-transporters

What are two types of Antiporters and how do they work?

• Na/Ca exchanger - keep Ca low inside

• Na/H exchanger. -regulates pH - H out

These work in opposite directions, where one ion goes inside, and the other out

What are the 3 types of co-transporters and how do they work?

• Na/K/Cl co-transport - Cl inside

• K/Cl - co-transport - regulates Cl out

• Na/NTs co-transport - synapses

These work by ions moving in the same direction in or out

How are ion gradients established?

• ion gradients 

• ion channels

Why ion channels?

They allow ions to diffuse down their [C] gradients high to low and are selectively permeable

Is resting membrane pot Vm = 0?

NO! thats why we have ion channels, they control RMP

What if we had no ion channels?

Then no e- potential - so no resting membrane

How is the RMP created?

K moves across [C] gradient - chemical pot

Then ± charges re-distribute and causes to build up e- potential around membrane

will lead up and countinue to flow until eq.potential of K = negative

then Na also flows and has + potential(not exactly eq.pot in the cell)

Chemical potential is the

flow of ions

Electrical potential is the

flow of charges

The Nernst Equation

z = ion charge

ion out = outside ion [C]

ion in = inside ion [C]

If there was only one type of ion channel then resting

Vm equals to eq.potential of that ion

What is the E ion for the major 3 ion types?

K = -80 mV

Na = 62 mV

Cl = -65 mV

The smaller the ion-out/ion-in ratio is, the

more negative the Eion is

Goldman=Hodgkin-Katz equation

Vm = 62log(permeability out of ions)/(permeability of ions in)

What is an assumption of Goldman equation?

Cl = 0 

In a cell, Vm is closer to the eq.potential of the ion that is

more permeable

if PK/PNa = 40, then

Vm = closer to K, so more (-)

What are 2 categories of ion channels?

• Leakage channels

• Gated ion channels

What do voltage-gated ion channels do?

They open at the action potential, increasing permeability of their ion

How do the Na voltage gated ion channels work?

Opens early when a positive stimulus comes by to trigger a more + potential and opens Na quickly

How do the K voltage-gated channels work?

Open late after the Na channel and slow to close - slow to open and close, lead to hyperpolarize

What are the 4 steps of the AP

• Rising Phase = Na increases

• Overshoot = Na at max, K opens

• Falling = Na decreased and K reaches max

• Undershoot = Na inactive and K decreases

What are the two feedback groups of the AP

• + feedback = Na increase → keeps opening and opening(until it eventually has no more Na channels to open) = self-sustaining

• - feedback = K channels open to hyperpolarize membrane and restore to RMP

How does the AP Propogate?

By the nodes of Ranvier - jumps → as the signal moves through the axon, it activates the next channels(because of Na) and decreases in past channels(because of K)

What are the 5 steps of the AP propogation?

• AP starts at axon hillock - Na channels

• Cytoplasm is conductive to allow Ap to move

• Depolarization of volt-gated Na channels downstream 

• repeat of process to propagate AP

• AP moves to terminal via Na and not backwards due to K

What are the 3 types of ligand-gated channels?

• NTs

• Proton(H+)

• Second messengers - Ca, cAMP

What are thermoreceptors?

Detect changes in temperature, hot or cold - also capsaicin for heat receptors

What are mechanoreceptors?

Detect pressure stimuli, sound, distortion of cytoplasmic membrane.

Synaptic transmission needs:

AP and synaptic potentials - pre and post synapse stuff

What are the 2 types of synapses?

Electrical and Chemical

What are electrical synapse?

Flow of ions - narrow gaps, very closely connected synapses, no vesicles and low receptor selectivity 

What are chemical synapses?

Flow of NTs → have larger gap junctions, vesicles, and more selective receptors 

Why are electrical synapses special?

They are muchhh faster than chemical ones - minimal delay in sending signal

With electrical synapses, there is increased(word for togtherness)

synchrony and connection of communication → bidirectional

What are 2 unique things about chemical synapses?

Greater gap and specialized receptors on post-synapse

What are the 6 events during pre-synapse?

• AP comes to axon terminal

• NTs made and ready in vesicles

• Ca channels open up by depolarization

• [Ca] influx

• Ca and synaptogmins cause vesicles to fuse with synaptic membrane

• NTs leave via exocytosis 

Why is Ca so important?

Ca triggers NT release - without it, no signal to post-synapse - needed and is sufficient for synaptic transmission

What are the 6 post-synapse events?

• NTs exocytosis into synapse

• NTs bind to post-synaptic receptors

• open/close channels

• IPSP/EPSP

• NTs removed from synapse

• NTs stored into vesicle on pre-synapse

What are the 2 types of NT receptors?

Ionotropic and metabotropic

What are ionotropic receptors?

They are like ion channels - open once receptor binds → 3 step process

What are metabotropic receptors?

Use GCPRs to open - ligand gated and 4-5 steps

What are the differences between iontotropic and metabotropic receptors?

Ionotropic = faster, use nicotinic acetyl, and encode info

Metabotropic = slower, musacrinic, and excitability and NT release 

What are excitatory synapse?

Use glutamate, +, AMPA receptors, and Na flow to dep.

What are inhibitory synapses?

Use GABA, -, Cl flow, and hyperpolarize

What is the threshold for AP firing?

-40mV

What is synaptic summation?

When many signals come in at once to fire AP

What is synaptic temporal sumamtion?

When signals come in one after the other - timed summation

What are the 2 parts of a neuron?

Soma and neurite(axon/dendrites)

What are 3 types of neurons Cajal found?

purkinje, pyramidial, ganglion

Why are pyramidial neurons special?

They can be located and branch into many areas of the brain

Non-pyramidial neurons are

interneurons - one area

Bitufted neurons

have 2 sides f dendrites, ex. pyramidial neurons

What are some neuron axon shapes?

Basket - round axon shape

Chandelier = axons fall 

What are some gene classifications of neruons?

• GABA = Parvalbumin, somatostatin

• Ca = Calbindin, calretinin

• VGAT, GAD = GABA (package and making)

• ChAT = Ach

What are the 4 types of neuron firing?

• non-acomodating = doesn’t increase/decrease = same

• accomodating = firing decreases with time

• Fast spiking = fast burst then decreases

• Irregular = no certain way or pattern

What firing do pyramidial cells use?

use glutamate, VGLUTS, and all 4 types

What firing do basket cells use?

GABA, parv, VGAT, GAD = fast and non-accomodating

What do martinotti cells use to fire?

GABA, Somato, VGAT, GAD = reg. and accommodating

What is the knee jerk reflex?

Uses the motor and sensory neurons to jerk knee when hit

What are the steps to the knee jerk reflex?

• hit knee, sensory neurons active in spinal cord - internuerons - inhibit flexor

• motor neurons activate extensor, relax flexor

• leg extends

What are 5 ways to study neurons?

• Extracellular recording

• intracellular recordings

• Ca functional imaging - use GFP, Ca, calmodulin binding etc

• Using Gene tools like Cre-LoxP, cre recombinase excisons 

• Scaning tools

What is synaptic plasticity?

Strengthen of connections over time

What are the 2 types of plasticity?

LTM and STM

What is STM?

Short-term - so after 1 AP = facilitation

What does STM use?

increases Ca = more NTs in pre-synapse to allow AP firining

What is synaptic depression?

What increases tetanic stimulation arises, depletion of vesicle pool, less NTs to leave, and depression of AP

What is post-tetanic potentiation?

when increase tetanic stimulation lets more Ca in → instead of depletion

What is LTP?

Long-term potentiation - on a longer scale → lasts for a longer time