Principles of Neural Signalling

Question 1

Why do we study neural signalling? (3) reasons

Answer 1

1. all brain functions stem from neuronal signalling
2. all brain diseases directly or indirectly stem from altered signalling
3. all drugs that are used to treat psychiatric disorders work by modifying neuronal signalling (like the metabolism of NT’s and synaptic transmission)

Question 2

what is the neuron doctrine?

Answer 2

proposed by waldeyer; claimed that the neuron is the anatomical and physiological unit of the nervous system (i.e. fundamental unit) and coined the term ‘neuron’ in neural science
Ramon y cajal’s work supported the neuron doctrine by showing histological studies of brain tissue showing that all neurons are functionally connected to one another

Question 3

what is the main difference between the electrical signals produced in the dendrites vs. the axons?

Answer 3

in the dendrites theres smaller electrical signals produced called EPSP’s
in axons, AP’s are produced and are fast and short lasting

Question 4

What is the properties of the neuron at rest?

Answer 4

inside has negative net charge due to differences in ion concentrations and permeabilities (outside has net positive charge)
at rest its highly permeable to K+
- this is maintained via active transport systems like sodium potassium pump

Question 5

What is the movement of ionic currents in neurons?

Answer 5

• when cations like potassium flow out of the neuron cell it is called an outward current
• when the cations are flowing into the cell its a inwards current
• when ions are moving into or out of membrane they require channels for that specific ion (pathway that allows certain ions to get across the membrane)

Question 6

What are voltage gated channels?

Answer 6

they are specific ion channels that are sensitive to changes in the membrane potential (voltage change)
- usually the ions go down their concentration gradients, sodium flows inwards, calcium flows inwards and potassium flows out of the cell
opening of the channels is called activation while closing is called deactivation

Question 7

How are channels formed (channel Genesis)?

Answer 7

1. channels are synthesized by TRANSLATION of mrna to protein subunits (making mrna into protein)
2. subunits are assembled and moved into the membrane where they mature and develop appropriate kinetic properties of activation and deactivation

Question 8

What happens to a mutation in gene that is involved in synthesis of channels?

Answer 8

mutation of genes encoding channel proteins will change kinetics of activation and deactivation of the channels
- this can lead to abnormally fast or abnormally slow channel kinetics and will make neurons and muscle cells more or less excitable leading to specific disease

Question 9

what is an example of a mutation in the voltage gated Na+ channel?

Answer 9

cause generalized epilepsy with febrile seizures due to slower INACTIVATION of Na+ current

was treated with oral diazepam to enhance inhibitory transmission

Question 10

What is the difference between local and general anesthetics?

Answer 10

local anesthetics: block voltage gated Na+ channels to block pain transmission i.e. novocaine and lidocaine
general anesthetics: induce unconsciousness for surgery; like propofol which potentiates GABA receptor activity and blocks Na+ channels

when na+ channels are blocked theres no depolarization and no AP generated

Question 11

Which portions of the axon conduct action potentials?

Answer 11

the unmyelinated portions called nodes of ranvier which has high density of na+ channels and spikes conduction velocity down an axon

Question 12

What is multiple sclerosis and how is it diagnosed?

Answer 12

its an autoimmune disease where the own immune system attacks myelin thinking its foregin antigen
- its diagnosed through:
optic neuritis in eyes, ataxia in movement (lack of muscle coordination) and muscle weakness overall
it has to do with poor conduction of AP’s

Question 13

What are the 10 steps in synaptic transmission?

Answer 13

1. transmitter is synthesized and then stored in vesicles
2. an action potential invades the presynaptic terminal
3. depolarization of the presynaptic terminal causes opening of the voltage gate ca2+ channels
4. influx of ca2+ through channels
5. ca2+ causes vesicles to fuse with presynaptic membrane
6. transmitter is released into the synaptic cleft via exocytosis
7. transmitter binds to receptor molecules in post synaptic membrane
8. opening or closing of post synaptic channels
9. post synaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell
10. retrieval of vesicular membrane form plasma membrane/reuptake/enzyme degradation

Question 14

What are excitatory postsynaptic potentials (EPSP)’s?

Answer 14

caused by glutamate being released from the presynaptic cell and opening up voltage gated sodium channels
it causes increase in voltage in the neuronal dendrites of the post synaptic cell and can lead to an AP if they’re summated

Question 15

What are inhibitory postsynaptic potentials (IPSP)’s?

Answer 15

cause by GABA being released into the post synaptic cell and opening up voltage gated chloride channels which cause hyperpolarization of the postsynaptic neuron and no firing of AP (inhibiting)

Question 16

What are ligand-gated channels? What are the two most important ones for glutamate?

Answer 16

• they are channels that are sensitive to binding of specific chemical transmitters (i.e. specific neurotransmitters)
• the glutamate channels that are most important are the
  1. NMDA receptors
  2. AMPA receptors
• these open up when glutamate binds to them

Question 17

How and when do AMPA and NMDA receptors become activated?

Answer 17

AMPA receptors can be activated at rest, whenever glutamate binds to it, it opens up and takes in sodium to the post synaptic membraned

NMDA receptors are “coincidence detectors” meaning to be activated, they require presynaptic depolarization AND post synaptic depolarization to unblock the channel

At rest the cell is not depolarized and NMDA receptors are blocked by mg2+

• When the presynaptic cell releases a lot of glutamate and sodium, it startes to depolarize the post synaptic cell (bc the presynaptic is excited)
• when the post synaptic neuron is depolarized to a certain extent, the NMDA receptors open and mg2+ unblocks the channel, and glutamate binds to it and lets in CALCIUM into the post synaptic membrane causing even MORE depolarization –> this is key to LTP

Question 18

What is excitotoxicity?

Answer 18

it is overstimulation of glutamate receptors that leads to excessive calcium entry and neuronal death

Question 19

what happens during a stroke and excitotoxicity?

Answer 19

during a stroke, blood supply is compromised and blood supply is what gives energy to get rid of the calcium that is excess; therefore excessive glutamate levels will occur same with over excitation and intracellular calcium accumulation which will KILL neurons

the energy that is normally needed is to supply glial cells (astrocytes) with energy to buffer glutamate by transporting it away from extracellular space

Question 20

What are 3 psychiatric disorders that are linked to perturbed neurotransmission?

Answer 20

1. depression –> reduced synaptic levels of NE and serotonin … treated with SSRI’s and antidepressants like prozac or reboxetine for NE boost
2. schizophrenia: associated with excess dopamine transmission… treated w drugs like clozapine that block dopamine receptors (D2 receptors)
3. anxiety disorders: treated with drugs that enhance GABA receptor function to promote synaptic inhibition like benzodiazepines and valium OR drugs that block reuptake of serotonin like prozac

Question 21

What is the hierarchy of signalling inside neurons?

Answer 21

1. transmitters and g-proteins are sitting at the membrane to get activated
2. once activated, they release a bunch of second messengers like cAMP, cGMP …etc..
3. Then the second messengers activate the third messengers which are protein kinases (add phosphate to proteins) or protein phosphotases (removes phosphate from proteins)
4. these kinases/phosphotases of proteins can lead to regulate multiple processes like: protein synthesis and gene expression, ion channel activation/inactivation, transmitter metabolism of NT’s, receptor trafficking, synaptogensis(formation of new synapses), and learning and memory

these all result in LONG TERM REGULATION

Question 22

What are 5 general features of signal transduction i.e 5 downstream effects of 2nd and 3rd messengers?

Answer 22

1. signal amplification: cells robustly respond to weak signals
2. pleiotropy: one extracellular signal elicits many responses
3. integration: numerous molecules interact with each other
4. specificity: neurons distinguish many signals and respond to a few
5. longevity of effects: gene expression and protein synthesis may be altered

Question 23

how are enzymes modulated by g-protein coupled receptors?

Answer 23

1. a neurotransmitter binds onto a receptor (enzyme) that could be a beta adrenergic, or a D1/D5 dopaminergic receptor
2. this causes GDP to turn into GTP in the G-protein and an alpha subunit discharges from its other subunits and activates another enzyme downstream responsible for synthesizing a second messenger (i.e. cAMP) [gives its GTP to it]

Question 24

Describe the process of activation of PKA and transcription? draw this in notebook

Answer 24

1. a NT binds to first transmitter receptor (e.g. beta adrenergic)
2. this activates the g-protein and dislodges the alpha protein and it gives energy to another enzyme which produces cAMP as second messenger
3. the cAMP helps turn inactive PKA subunit into activated pKA in the cytosol
4. the activated PKA then travels through the nuclear membrane and into the nucleus where it phosphorylates (removes phosphate) inactivated CREB into CBP (CREB binding protein) which is activated, phosphorylated CREB
5. the CBP then causes DNA transcription and then translation in cytosol

Question 25

Where are the pleasure centres of the brain located?

Answer 25

mainly in nucleus accumbens and VTA (ventral tegmental area)

Question 26

What is the reward circuit of pleasure?

Answer 26

VTA is the primary source of dopamine, when we experience pleasure, dopamine is released from VTA to different areas of the brain including: nucleus accumbens, hippocamps + amygdala, and prefrontal cortex

the prefrontal cortex will use dopamine to regulate organization of future behavior and motivation of behavior

the hippocampus and amygdala will provide the emotional overtone and create associations between the stimulus and the feelings (learning + emotions)

Question 27

What role does CREB play in addiction?

Answer 27

CREB consolidates the memory linking substance seeking behaviors with acquisition of substance and aims to obtain more substance and pleasure and makes it stronger

CREB also enhances non-harmful learning associations

remember that CREB is responsible in its active form to cause transcription and form long term results

Question 28

How does dopamine increase CREB levels and aid in drug addiction?

Answer 28

after we experience pleasure, dopamine increases and activates CREB inside of neurons, this causes euphoria, anorexia, insomnia and hallucinations when going on for too long