Midterm 2 Flashcards
Luigi Galvani
Observed that a frog leg twitched during an electrical storm. He concluded that the NS used electricity to communicate and he was partially correct
Otto Loewi
First evidence of chemical communication involvement in neurocommunication
- Stimulated the vagas nerve (slows rate of heart contractions. He found that another heart in the same solution also had a reduced rate of contraction even though its vagus nerve was not directly stimulated.
- He concluded that there must be a chemical release in the first heart that was affecting the other heart
- NEEDS BOTH ELECTRICAL AND CHEMICAL COMMUNICATION
chemical - ACh
What are the only excitable cells types?
neurons and muscle cells
these are the only cells with voltage gated sodium ion channels
What factors can lead to a graded potential occurring ?
Chemical (NT receptors)
Mechanical (stretch receptors)
What is the strength of the stimulus coded by?
The number/frequency of action potentials
Hodgkin-Huxley Model
Described the ionic basis of the AP - considered the most important achievement in cellular neurophysiology.
Mathematical + biophysical model of the AP
- the textbook model
- used squid axons
Graded potentials
Are variable with magnitude and duration which depends on strength and duration of the triggering event
Spread passively (no channel opening outside the point of origin, decreminating with distance from point of initiation
Travel over short distance
Channels during Resting
Na+ voltage activated gate is closed, Na+ inactivation gate is open. Channel is closed but not inactivated
Channels during depolarization.
Na+ flows into the cell because both the Na+ voltage activated gate and inactivation gate are open.
Channels during repolarization
Na+ voltage activated gate is open but the inactivation gate is closed and thus Na+ no longer flows into the cell.
K+ voltage gate is open and K+ moves out of the cell
Absolute refractory period
Channels during hyperpolarization
Na+ voltage activate gate is closed, the Na+ inactivation gate is open. No Na+ flows. K+ voltage activated gate is open.
Relative refractory period
Due to the K+ activation gate still being open and letting K+ out. The neuron needs more of a depolarizing stimulus to reach threshold for an AP to be generated during this period
How to speed up the nerve impulse?
Make the ions bigger in diameter or prevent ions from the leaving the axon by covering much of it with myelin
Group C fibres
Carry sensory information. They are unmyelinated, small diameter, and thus slow conducting
Include postganglionic fibres in the ANS and nerve fibres at the dorsal roots.
How do neurons generally make signals from distant synapses on dendrites for meaningful?
Larger PSP generated as distant synapses
signal boosters - VG Ca2+ channels - allow Ca2+ in to further encourage the cell to reach threshold
Where is an action potential initiated in neuron?
In the axon hillock - dense area of ion channels. There are no ion channels in the soma
How do touch sensory receptors work?
There is a dendrite wrapped around hairs. Displacement of hairs open stretch-activated channels in the dendrites membrane. When the channels open they allow an influx of Na+ ions sufficient to depolarize the dendrite to its threshold level
What is a renshaw loop ?
The axon collaterals of motor neurons will synapse with a renshaw cell (interneuron) . which then innervates the motor neurons
Indirect inhibition through renshaw interneuron controls motor neurons
Electrical synapse
Direct cytosolic (electrical conducting) bridges between cells (Na+ flows through)
Very fast but not very plastic (not a lot of modulation going on.
Not common in the mammalian brainy,
although invertebrates have many. Heart has many.
Chemical synapse
Not as fast as electrical synapse but very plastic (in the number of receptors, amount of NT, etc)
How many classical NTs are there versus neuropeptides?
7 diff classical NT’s
100 diff chemicals that are neuropeptides
How does the release of NT from the presynaptic neuron occur?
AP arrives at the axon terminal –> depolarization from the sodium influx activates voltage gated calcium channels – leads to calcium influx. Increase in intracellular calcium triggers the vesicles to fuse with the presynaptic neuron membrane – get exocytosis of NT
When more action potentials occur - what happens at the synapse?
Get MORE calcium influx which means MORE NT is released
Why can magnesium chloride be used as an anaesthetic?
When applied to body, it will be influxed into the cell instead of calcium – don’t get fusion of the NT vesicles with the membrane - don’t get exocytosed
Ionotropic receptor?
Ligand gated ion channel
Faster than metabotropic
Metabotropic receptor?
GPCR
The receptor type and ligand bind ultimately determines what effect the NT will have on the cell
Slower than ionotropic
Neurotransmitter
Chemical messenger used by neurons
A NT must be made or present in the cell that is releasing it.
The released chemical must be capable of producing an effect on its target (
Neurotransmitter
Chemical messenger used by neurons
A NT must be made or present in the cell that is releasing it.
The released chemical must be capable of producing an effect on its target (so the target MUST have receptors)
Effect of the chemical must be able to be mimicked by the exogenous application of the same or similar substance (response mimicked)
There should be a mechanism to remove or inactivate the NT when its work is done
Neuropeptide
Peptides that do not act directly as NTs but rather increase or decrease the action of an NT
Synthesized in the cell body of a neuron
Act usually as neuromodulators
>100 have been identified
Often co-localized with classical NTs and act as neuromodulators
Dale’s Exclusion Principle
States that although different NT’s can be produced at different synapses within the brain, idvl neurons are capable of releasing only one classical NT
A couple rare exceptions - co-release of GABA-glycine, Ach - glutamate, dopamine-glutamate
How is NT cleared from the synapse?
receptor desensitization
elimination of active NT from the cleft
- diffusion of NT away from the synapse
- inactivation of NT by enzymatic degradation
- remove of the NT by glia-uptake or re-uptake mechanisms
Desensitization of ionotropic receptor
Typical in the Nicotinic Acetylcholine receptor
NT is released but it might not activate the receptor anymore
May bind but the receptor will not be activated/opened up. Won’t let ions through.
temporary
Homologous Desensitization of metabotropic receptor?
Activated receptor gets phosphorylated —-able to become endocytosized – receptor is removed from the membrane
Heterologous desensitization of metabotropic receptor?
Desensitization occurs as a result of phosphorylation of one type of receptor as a result of kinases by another. Receptor becomes less responsive
How is acetylcholine made?
Made from dietary choline and acetyl CoA by choline acetyl transferase (ChAT).
Then degraded by acetyl cholinesterase into acetate and choline
Acetylcholine is the NT released at the neuromuscular junction
What receptors does acetylcholine bind to?
Ligand gated ion channels - nicotinic receptor
GPCR - muscarinic receptor
Where is acetyl choline produced in the brain?
Basal forebrain and brainstem
Projeccts to hippocampus, amygdala, cerebral cortex (find ACh receptors here)
Acetylcholine and disease
Involved in learning and memory
Decline associated with Alzheimers disease - specifically in the hippocampus there is not enough release of ACh
Monoamines
Include catecholamines (dopamine, NE, E), indolamines (serotonin, melatonin), and imidazoleamines (histamine)
Dopamine
Made from tyrosine
Produced in 3 systems
mesolimbic, mesocortical, mesostriatal
Component of the reward pathway - makes you feel good
Associated with Schizophrenia (excessive dopamine release)
Mesolimbic and Mesocortical pathways
Dopamine production
From the ventral tegmental area -projects to the nucleus acumbens, amygdala, hippocampus, and cortex
Schizophrenia - excessive dopamine produced here is associated with Schizophrenia
Mesostriatal pathway
Dopamine release
From the substantia nigra (basal ganglia) - projects to striatum (caudate and putamen)
Loss associated with Parkinson’s Disease (not enough dopamine release)
Providing L-Dopa to these patients may help!
Receptors for Dopamine?
5 receptors, all GPCR!
Pathway to create Dopamine
Tyrosine–tyrosine hydroxylase–> L-Dopa–> DOPA decarboxylase –> Dopamine
Norepinephrine
Made from dopamine
Dopamine –> dopamine b-hydroxylase –> NE
Post ganglionic neuron in the sympathetic NS
If you have Parkinson’s you may not have enough NE either because NE is derived from dopamine
Where is NE synthesized in the brain?
Locus coeruleus, lateral tegmental area, dorsal medullary group
Projects widely (cortex, cerebellum, hippocampus, etc)
Action of NE?
Modulates physiological states:
- mood (anti-depressant target)
- ADHD (attention)
- sleep/wake
- sexual behaviour
- arousal
- stress reactions
- cognitive functions
Can bind to alpha1,2 or beta 1,2 receptors
Serotonin
5-HT - 5hydroxytrypotomine
Made from tryptophan
Produced by Raphne nuclei and projects widely in the brain
Has 7 classes of receptors (13-15 in total)
1 ligand gated channel - all others are GPCR
What does serotonin regulate?
sleep, mood, anxiety
Histamine
Made from the amino acid histidine
Made in the tuberomammillary nucleus of the hypothalamus
Plays a key role in arousal
Used for allergies - anti-histamines (first generation allergy meds made people drowsy because they were able to cross the BBB and mind to receptors in the brain) - second generation anti-histamines are not able to cross the BBB and therefore don’t cause drowsiness
Histamine receptors
Has 5 receptors. 4 in the brain
3 GPCR and one Cl- LG ion channel
Projects widely - cerebellum, brainstem, cortex
Amino acid transmitters
Most common class of NT in the CNS
Amino acid transmitters
Most common class of NT in the CNS
- include glutamate, aspartate, GABA, and glycine
Glutamate
classical NT
Amino acid transmitter
there are 4 types of glutamate receptors (IGPCR)
Involved in learning and memory
after a stroke - can get cell death due to overactivation - too much glutamate
excitatory
GABA
amino acid transmitter
inhibitory
3 types of GABA receptors (1 LG, 2 GPCR)
Opioid peptides
Enkaphalines and endorphins. Natural pain killers. Endogenous morphines. Bind to opioid receptors
Pituitary peptides
Oxytocin, vasopressin
Endocannabinoids
endogenous molecules that bind to cannabinoid receptors
They are synthesized as needed and act as retrograde messengers (released from the post-synaptic cell - bind to CB1 and CB2 receptors on the presynpatic cell
Play a role in memory, appetite, pain, anxiety
Most common receptors are CB1 and CB2 (GPCR)
CB1 is activated by THC
Retrograde messenger
Molecule released from the post-synaptic neuron that binds to the pre-synaptic neuron
ex. cannabinoids, nitric oxide
Purines
transmitter molecule
ex. adenosine - involved in sleep production. Caffeine prevents the binding of adenosine from its receptor
Gases as transmitter molecules
ie nitric oxide - a retrograde messenger (Post- pre) that enhances the pre-synaptic release of glutamate. Involved in memory
Also important for smooth muscle relaxation
Zinc can also act as a transmitter as an ion
Habituation
The overtime decreased response to steady or repeated stimuli
NS is interested in change rather than constant stimuli
Stimuli still there but you don’t perceive them - why?
With repeated stimulation, the Ca2+ VG channels in the presynaptic terminal desensitizes. Normally with AP incoming it triggers Ca2+ channel to open causes influx of Ca2+ causing vesicle fusion to the membrane.
With VG Ca2+ channel desensitized - get less Ca2+ influx and therefore less NT release into the synapse.
DECREASED RESPONSE
Sensitization
Exhibiting greater responses based on experience. ie horror movie scare build up
In sensitization - Ca2+ has a larger effect - get more NT released from the synapse - larger response.
In the slug, the increase in Ca2+ was mediated by an interneuron receiving a sensory signal - causes it to relase serotonin which then reduces K+ efflux - prolonging AP in the sensory neuron (where the calcium is)
Shorter than habituation
Filopodia
branches of dendrites - formed that are constantly looked for new connections - become spines if the connection is meaningful
What is the effect of long-term habituation on synapses?
Decrease in synapses
What is the effect of long term sensitization on synapses?
Increase in synapses
Glutaminergic synapses
Very involved in learning and memory
Can involve ionotropic (LG ion channels) or metabotropic (GPCR) receptors
Ionotropic glutaminergic receptors
AMPA, NMDA
NMDA receptors
ionotropic glutamate receptor
Agonists: glutamate and NMDA
Willow allow Na+, Ca2+ in and K+ out of cell.
HAS A MAGNESIUM BLOCK THAT MUST BE REMOVED BEFORE IONS ARE ABLE TO PASS
HIGH CALCIUM PERMEABILITY
AMPA receptors
ionotropic glutaminergic receptor
Agonists: glutamate, AMPA
Will allow Na+ and a bit of Ca2+ in and then let K+ out.
NO MAGNESIUM BLOCK
LOW CALCIUM PERMEABILITY
Binding of glutamate in NMDA and AMPA receptors
Glutamate binds to both receptors on the postsynaptic neuron but initially only Na+ flows in (and K+ out) through the AMPA receptor as the magnesium block is blocking the NDMA receptor. This Na+ influx depolarizes the post-synaptic area, causes the release of the Magnesium block. This opens up the NDMA receptor and as such, both Na+ and Ca2+ are able to flow in.
Calcium then activates enzymes - leads to second messenger system activation - this can lead to retrograde signal regeneration
calcium-calmodulin (dependent kinase)
What causes the magnesium block to be removed on the NMDA receptor?
The depolarization caused by the influx of Na+ ions caused by the opening of the AMPA channel
How does calcium calmodulin protein kinase enhance excitability?
It mobilizes new AMPA receptors (more receptors)
It makes existing AMPA receptors more responsive (increasing their conductance)
- POSITIVE FEEDBACK LOOP
CREB
Ca2+ can activate cAMP responsive binding protein (CREB) which is a TF that binds DNA and promotes gene expression – lead to protein synthesis = ie. new receptors (long term plasticity)
cAMP and CREB
important for memory formation
Drug
A chemical substance of known structure, other than a nutrient or an essential dietary nutrient, that when administered to a living organism, produces a biological effect
Medicine
A chemical preparation, which usually but not necessarily, contains one or more drugs, administed from the intention of producing a therapeutic effect.
Contains substances besides the drug that make them more conveniant to take
Medicine contains the drug
