Cell Neuro Exam 3

Types of Neurotransmitters

1. Amino acids

2. Biogenic amines (monoamines)

3. Peptides

4. Acetylcholine

5. Gas transmitters and ATP

Amino Acid Neurotransmitters

Glutamate, GABA, glycine

Glutamate

Very common in the brain

GABA and Glutamate

often inhibitory

Biogenic amines (monoamines)

Serotonin

Catacholamines: dopamine, norepinephrine, epinephrine

Development of Catacholamine

Dopamine makes norepinephrine, which makes epinephrine

(tyrosine makes dopamine)

Serotonin

Made by tryptophan

Peptide Neurotransmitters

Endophrines and Substance P

Usually synthesized in the cell body and cleaved off from a larger precursor, put in vesicles

Acetylcholine (ACh)

made from acetyl-CoA and choline

Gas Neurotransmitters

NO and CO

Gas synthesized right in the postsynaptic membrane

Work quickly

How are many neurotransmitters made?

Many neurotransmitters are made in the cell body and are transported to the terminal through axoplasmic transport.

Axoplasmic transport

the process that moves things through the cytoplasm of a neuron’s axon in anterograde or retrograde

empty vesicles may also need to be transported from the terminal back to the cell body

anterograde

Transport from cell body to terminal and uses the protein kinesin

Kinesin

Protein used for anterograde transport

Dynein (MAP-1C)

Protein used for retrograde transport

Retrograde

Transport from the terminal to cell body

How does axoplasmic transport work?

• Transport uses microtubules

  • Microtubules have polarity in their tubulin components

  • Kinesin and dynein have a preferred polarity for the microtubule, which is opposite each other so that they move in opposite directions

  • Motor proteins bind a vesicle on one end, like the “head”, and has “legs” attaching to the microtubule. Each “leg” acts as an ATPase and hydrolizes ATP. The energy produced causes a conformational change in the “legs” which makes it step forward

• Axoplasmic transport can be regulated by the neuron, but not known how

Drugs with presynaptic effects

• Neurotransmitter release: Methamphetamine, Ecstasy/MDMA

• Neurotransmitter reuptake: Cocaine, Ritalin, SSRI

Methamphetamine

1. acts on transporter (which normally sucks dopamine out of the synapse), pushing dopamine into the synapse - reversing the transporter

2. dumps more dopamine from the terminal into the synapse

• causes increase in dopamine

Ecstasy/MDMA

• affects serotonin transporter and NE transporters

  • It makes serotonin transporter dump extra serotonin so you get a massive serotonin surge

  • (similar to methamphetamine on dopamine)

• Extra notes: increase in norepinephrine, affecting sympathetic nervous system, increasing body temp and dilating eyes. Can also cause you to run out of serotonin so that the next day don’t feel happy because used up serotonin

Cocaine

• Blocks the reuptake transporter for dopamine

• In the reward circuit, enhances dopamine release from ventral tagmental area to nucleus accumbens

Ritalin

Blocks dopamine reuptake (but not the same as cocaine) and norepinephrine reuptake

Selective Serotonin Reuptake Inhibitor (SSRI)

Interferes with reuptake of serotonin so that it sticks around longer

Drugs with postsynaptic effects

Nicotine, Psychedelic Drugs (LSD, psilocybin, mescaline), Marijuana-THC, opiates, alcohol, propofol, caffeine

Nicotine

Binds to the ACh (nicotinic) receptors in ventral tegmental area to act as an agonist stimulating them to release more dopamine in the nucleus accumbens (the pleasure pathway) - causing addiction

Psychedelic drugs

LSD, psilocybin, mescaline

• Bind at a type of serotonin receptor to mimic it (doesn’t act on pleasure circuit-nonaddictive)

Marijuana-THC

• Binds to two primary G protein-coupled receptors: one is involved in immune responses and the other has psychoactive effects. The receptors are already present in the brain, peripheral nervous system, to help maintain physiological balance

• G protein mediated

Opiates

Heroin, Morphine, Codeine

• endogenous opiate receptors exist and they bind to endorphins and enkephalins, which are natural neuromodulators

  • Opiod receptors belong to G-protein mediated system

• Heroin made from morphine is more lipid soluble so gets through blood brain barrier

• Addictive properties due to action on the pleasure pathway (ventral tegmental to nucleus accumbens). Naturally, GABA slows down dopamine production and opioids inhibit GABA that come in to the ventral tegmental area.

  • Essentially, opioids inhibit the inhibitors to the pleasure circuit

Alcohol

• Acts on GABA receptors to enhance their inhibitory effects in the brain, making it harder for the neuron to fire

• Also inhibits the voltage gated Ca2+ channels needed for neurotransmitter release - slowing neural communication

• So it inhibits many circuits

Propofol

a GABA enhancing drug and a tranquilizer - makes it harder for the neuron to fire

Caffeine

•  Binds at adenosine receptors in the brain

• Adenosine receptors are found on the inhibitory neurons. Adenosine activates those inhibitory neurons, which have inputs to neurons promoting wakefulness. Adenosine inhibits wakefulness.

  • Caffeine blocks adenosine receptor, promoting wakefulness

• Adenosine can also activate sleep promoting neurons in the hypothalamus

  • So caffeine blocks these so it blocks sleepiness

Where is threshold at its lowest?

The neuron spike initiation zone, due to an abundance of voltage gated Na+ channels

What does PSP amplitude depend on?

1. Initial amplitude

2. How big the amplitude is once it has reached the SIZ - depends on length constant and time constant

High length constant

high membrane resistance and low internal resistance (large diameter)

high time constant

high membrane resistance and high membrane capacitance

Long lasting PSP

High time constant and ?high length constant?

EPSPs and IPSPs affect on Vm at SIZ

EPSPs add to the SIZ to push Vm closer to threshold, while IPSPs subtract from this Vm and pull it away from threshold

Spatial summation

all the PSPs arriving at the SIZ at the same time, with their various amplitudes

Temporal summation

how long the PSPs last and whether any parts of them are present at the same time to add to the change in Vm

How can I weigh some inputs to the neuron more heavily than others?

1. Put the more important input on a larger diameter dendrite

2. Put the more important input closer to the SIZ

3. Put the more important input on the SIZ

Difference between summation and homosynaptic facilitation

• Summation is about the receiving postsynaptic neuron and how it adds up PSPs, whereas homosynaptic facilitation is about how the presynaptic neuron releases more neurotransmitters producing a larger postsynaptic response

• In facilitation, the Vm drops back to normal between PSPs

Homosynaptic Facilitation STeps

• the presynaptic cell has Ca2+ linger in its terminal. It lets in Ca2+ during the 1st action potential and then it releases the neurotransmitters.

• Here, some Ca2+ lingers in the terminal so taht when the presynaptic clel fires again, Ca2+ comes in again and adds to the lingering Ca2+

  • So there are more neurotransmitters released and the postsynaptic cell shows a larger PSP

• If you do this again, lingering Ca2+ from the first action potential adds to Ca2+ front eh second action potential so you get an even larger PSP

• Over time the Ca2+ gets sequestered in the terminal and the levels go back to the original. In another neurotransmitter release, the PSP size will go back down

Heterosynaptic facilitation

• involves 3 neurons

• Normally: If you stimulate B, you see a PSP in A

• Heterosynaptic facilitation: If you stimulate C then B, C causes Ca2+ channels in B to open (or be more easily opened), so that when you stimulate B it releases more neurotransmitters onto A, where you record a larger PSP

Posttetatnic Potentiation

Ca2+ leaks back out from where its held (mitochondria, ER) after an initial stimulus and n.t. release. So, after time, Ca2+ levels in the terminal are quite high and if the presynaptic cell receives another stimulus, it releases more neurotransmitters

When do NMDA channels open?

1. The cell is strongly depolarized - to knock of Mg2+

2. Glutamate is present

What does NO gas do to the presynaptic cell in LTP?

• Cause more glutamate release

• It makes more K and AMPA channels with preexisting channels

• It makes K and AMPA more sensitive to glutamate

Long Term Potentiation

• NMDA receptors also bind glutamate and open for K+, Na+, and Ca2+

  • But it only opens if the cell is strongly depolarized. The receptor gets plugged by Mg2+, so it needs a strong depolarization to knock off the positive ion

• When Ca2+ comes into the postsynaptic cell, it activates NO synthase, which creates NO gas

  • NO gas diffuses through membranes easily and enters the presynaptic cell, leading to:

    • More glutamate release

    • It makes more K and AMPA channels with preexisting channels

    • It makes K and AMPA more sensitive to glutamate

• End result: stronger synapse

K and AMPA receptor funciton

K and AMPA receptors bind glutamate. They open for K+ and Na+, causing EPSPs

NO gas function in LTP

• NO gas diffuses through membranes easily and enters the presynaptic cell, leading to:

  • More glutamate release

  • It makes more K and AMPA channels with preexisting channels

  • It makes K and AMPA more sensitive to glutamate