NEUROSCIENCES
ION CURRENT FLOW
This will be in the exam!
membrane potential & reversal potential is in the cell. So you think of which way the ions have to go to bring
the membrane potential towards their reversal potential.
negative charge: positive ions flow inward
positive charge: positive ions flow outwards
You hold the membrane potential at -35 mV in a patch-clamp experiment. What happens to the ionic current
when you puff neurotransmitter on the cell that fully opens neurotransmitter receptors with maximal
conductivity?
Given: the reversal potentials of Na+: +65 mV, K+: -100 mV, Cl-: -50 mV
Cion = gion x (Vm – Erev ion)
gion = 1 (maximal conductivity)
Vm = -35 mV
Erev = Na+: +65 mV, K+: -100 mV, Cl-: -50 mV
CNa+ = 1 x (-35 - 65) = -100 (positive charge flow inward)
CK+ = 1 x (-35 - -100) = -35 + 100 = 65 (positive charge flow outward)
CCl-= 1 x (-35 - -50) = -35 + 50 = 15 (negative charge flow inward = positive charge outward)
-100 + 65 + 15 = -20 : Overall positive charge flowing inward
EXCITATION AND INHIBITION
Erev is set by the electrochemical gradient, which can differ from cell to cell. This determines if an synapse is
excitatory or inhibitory.
To determine if a synapse is excitatory or inhibitory you do the above calculation. If you open up all the
channels for infinite time, could you reach the action potential threshold. Yes? Excitatory. No? Inhibitory.
Erev > threshold for an action potential: excitation
Erev < threshold for an action potential: inhibition
,TRANSMISSION
,Electrical synapse: Direct exchange of ions and small molecules by passive flow between the pre- and
postsynaptic cell. This is extremely fast, bi-directional and is used for synchronization of cells in a network and
fast responses.
Chemical synapse: Indirect transmission of electrical signals trough chemical signaling molecules
(neurotransmitters). This is a bit slower, mostly one-directional but tunable and there is a variety of
neurotransmitters available (so not only small molecules). It is used for regulated activity and plasticity
(learning, memory).
Plasticity: tunable transmission by chemical synapses; amplification, suppression and alteration of signals.
Small-molecule transmitters are locally recycled and taken up into small clear core vesicles. This makes them
vastly available.
Peptide transmitters are produced in the nucleus of the neuron, and are transported to the synapse
(40cm/day) in dense core vesicles. This makes them less available for continuous firing. Also, dense core
vesicles require prolonged calcium influx for fusion.
Fusion of synaptic vesicles to the membrane is divided in steps: docking; priming; calcium sensing.
During the fusing a SNARE complex is formed by the Synaptobreving on the vesicle binding to the Syntaxin and
SNAP-25 on the plasma membrane. Then the calcium sensors open and the calcium binds to synaptotagmin on
the vesicle which curves the membrane and brings the vesicle and membrane closer together.
NEUROTRANSMITTERS
SMALL-MOLECULE NTRS
Acetylcholine (ACh) – Neuromuscular junction. Many functions: secretion salivary cells; contraction skeletal
muscle cell; decreased rate and force of contraction of heart muscle cell.
This NTR is locally recycled and broken down by acetylcholinesterase (AChE).
AChE blockers (Sarin, Novichok) makes Acetylcholine last in the synaptic cleft, overstimulating the
nerves. This causes contraction of skeletal muscles and then respiratory & cardiac arrest. Can be
treated by blocking AChR receptors.
Nicotine (plant) is agonist for ionotropic receptor, Muscarine (fungi) is agonist for metabotropic
receptor. a-bungarotoxin (snake venom) and curare (plant) are antagonists of the nicotinic receptor.
Atropine (belladonna) is antagonist of the muscarinic receptor.
Glutamate mediates excitatory input in the brain.
It is terminated by uptake in glial cells by EAAT, where it’s turned into glutamine and brought back into the
presynaptic cell.
mGluRs are also expressed on the presynaptic cell and cause a negative feedback loop on glutamate release.
Excitotoxicity is caused by too much glutamate. Excess glutamate allows high levels of calcium ions to
enter the cells, which in their turn activate enzymes that damage cell structures. It can happen when
the synapse is blocked (tumor, stroke) and glial cells can’t take up the glutamate.
GABA mediates the most inhibitory connections in the brain.
It is produced out of glutamate with help of glial cells.
GABA-A receptor is a chloride ion channel which suppresses neuronal activity. GABA-B also suppresses
neuronal activity.
, Benzodiazepines (e.g. diazepam) and barbiturates cause a prolonged opening or more frequent
opening of the GABA-A receptor. Alcohol and other anesthetics have a similar effect. Picotoxin blocks
the GABA-A receptor and can be used to treat an overdose of barbiturates of benzodiazepines.
MONOAMINES
Catecholamines (dopamine, noradrenaline, adrenaline) are all synthesized from tyrosine. They are produced in
the brainstem with wide connections (also for serotonin and histamine). The wide connections modulate
neurotransmission and a wide variety of behavior. Dysregulation of these NTRs can lead to anxiety, depression
or obsessive behavior. Therefore these NTRs are common targets for antidepressants or anxiolytics.
Fluoxetine (Prozac) is an SSRI (selective serotonin reuptake inhibitor). It block reuptake of serotonin,
resulting in serotonin persisting longer when it is released.
NEUROPEPTIDES
Are produced from propeptides by proteolytic cleavage.
Endorphins are opioid peptides. They inhibit pain signals. It’s production is simulated by aerobic exercise
(runners high) and laughter.
Opioid receptors are targeted by morphine. It is one of the most potent anesthetics, but highly
addictive.
UNCONVENTIONAL NEUROTRANSMITTERS
NO gas and endocannabinoids are unconventional because they are membrane-permeable. They can’t be
stored in vesicles. These neurotransmitters are rapidly synthesized upon stimulation. These neurotransmitters
are also often released by the postsynaptic side of a classic neurotransmitter synapse to mediate retrograde
signaling. They do possess all other characteristics of neurotransmitters including selective receptors.
Endocannabinoids are lipid-based neurotransmitters and provide retrograde feedback.
IONOTROPIC METABOTROPIC (GPCR)
ACETYLCHOLINE Nicotinic AChR Muscarinic AChR
GLUTAMATE AMPA, NMDA, kainate mGluRs
GABA GABA-A GABA-B
MONOAMINES Serotonin receptors All others are GPCR
NEUROENDOCRINE
ION CURRENT FLOW
This will be in the exam!
membrane potential & reversal potential is in the cell. So you think of which way the ions have to go to bring
the membrane potential towards their reversal potential.
negative charge: positive ions flow inward
positive charge: positive ions flow outwards
You hold the membrane potential at -35 mV in a patch-clamp experiment. What happens to the ionic current
when you puff neurotransmitter on the cell that fully opens neurotransmitter receptors with maximal
conductivity?
Given: the reversal potentials of Na+: +65 mV, K+: -100 mV, Cl-: -50 mV
Cion = gion x (Vm – Erev ion)
gion = 1 (maximal conductivity)
Vm = -35 mV
Erev = Na+: +65 mV, K+: -100 mV, Cl-: -50 mV
CNa+ = 1 x (-35 - 65) = -100 (positive charge flow inward)
CK+ = 1 x (-35 - -100) = -35 + 100 = 65 (positive charge flow outward)
CCl-= 1 x (-35 - -50) = -35 + 50 = 15 (negative charge flow inward = positive charge outward)
-100 + 65 + 15 = -20 : Overall positive charge flowing inward
EXCITATION AND INHIBITION
Erev is set by the electrochemical gradient, which can differ from cell to cell. This determines if an synapse is
excitatory or inhibitory.
To determine if a synapse is excitatory or inhibitory you do the above calculation. If you open up all the
channels for infinite time, could you reach the action potential threshold. Yes? Excitatory. No? Inhibitory.
Erev > threshold for an action potential: excitation
Erev < threshold for an action potential: inhibition
,TRANSMISSION
,Electrical synapse: Direct exchange of ions and small molecules by passive flow between the pre- and
postsynaptic cell. This is extremely fast, bi-directional and is used for synchronization of cells in a network and
fast responses.
Chemical synapse: Indirect transmission of electrical signals trough chemical signaling molecules
(neurotransmitters). This is a bit slower, mostly one-directional but tunable and there is a variety of
neurotransmitters available (so not only small molecules). It is used for regulated activity and plasticity
(learning, memory).
Plasticity: tunable transmission by chemical synapses; amplification, suppression and alteration of signals.
Small-molecule transmitters are locally recycled and taken up into small clear core vesicles. This makes them
vastly available.
Peptide transmitters are produced in the nucleus of the neuron, and are transported to the synapse
(40cm/day) in dense core vesicles. This makes them less available for continuous firing. Also, dense core
vesicles require prolonged calcium influx for fusion.
Fusion of synaptic vesicles to the membrane is divided in steps: docking; priming; calcium sensing.
During the fusing a SNARE complex is formed by the Synaptobreving on the vesicle binding to the Syntaxin and
SNAP-25 on the plasma membrane. Then the calcium sensors open and the calcium binds to synaptotagmin on
the vesicle which curves the membrane and brings the vesicle and membrane closer together.
NEUROTRANSMITTERS
SMALL-MOLECULE NTRS
Acetylcholine (ACh) – Neuromuscular junction. Many functions: secretion salivary cells; contraction skeletal
muscle cell; decreased rate and force of contraction of heart muscle cell.
This NTR is locally recycled and broken down by acetylcholinesterase (AChE).
AChE blockers (Sarin, Novichok) makes Acetylcholine last in the synaptic cleft, overstimulating the
nerves. This causes contraction of skeletal muscles and then respiratory & cardiac arrest. Can be
treated by blocking AChR receptors.
Nicotine (plant) is agonist for ionotropic receptor, Muscarine (fungi) is agonist for metabotropic
receptor. a-bungarotoxin (snake venom) and curare (plant) are antagonists of the nicotinic receptor.
Atropine (belladonna) is antagonist of the muscarinic receptor.
Glutamate mediates excitatory input in the brain.
It is terminated by uptake in glial cells by EAAT, where it’s turned into glutamine and brought back into the
presynaptic cell.
mGluRs are also expressed on the presynaptic cell and cause a negative feedback loop on glutamate release.
Excitotoxicity is caused by too much glutamate. Excess glutamate allows high levels of calcium ions to
enter the cells, which in their turn activate enzymes that damage cell structures. It can happen when
the synapse is blocked (tumor, stroke) and glial cells can’t take up the glutamate.
GABA mediates the most inhibitory connections in the brain.
It is produced out of glutamate with help of glial cells.
GABA-A receptor is a chloride ion channel which suppresses neuronal activity. GABA-B also suppresses
neuronal activity.
, Benzodiazepines (e.g. diazepam) and barbiturates cause a prolonged opening or more frequent
opening of the GABA-A receptor. Alcohol and other anesthetics have a similar effect. Picotoxin blocks
the GABA-A receptor and can be used to treat an overdose of barbiturates of benzodiazepines.
MONOAMINES
Catecholamines (dopamine, noradrenaline, adrenaline) are all synthesized from tyrosine. They are produced in
the brainstem with wide connections (also for serotonin and histamine). The wide connections modulate
neurotransmission and a wide variety of behavior. Dysregulation of these NTRs can lead to anxiety, depression
or obsessive behavior. Therefore these NTRs are common targets for antidepressants or anxiolytics.
Fluoxetine (Prozac) is an SSRI (selective serotonin reuptake inhibitor). It block reuptake of serotonin,
resulting in serotonin persisting longer when it is released.
NEUROPEPTIDES
Are produced from propeptides by proteolytic cleavage.
Endorphins are opioid peptides. They inhibit pain signals. It’s production is simulated by aerobic exercise
(runners high) and laughter.
Opioid receptors are targeted by morphine. It is one of the most potent anesthetics, but highly
addictive.
UNCONVENTIONAL NEUROTRANSMITTERS
NO gas and endocannabinoids are unconventional because they are membrane-permeable. They can’t be
stored in vesicles. These neurotransmitters are rapidly synthesized upon stimulation. These neurotransmitters
are also often released by the postsynaptic side of a classic neurotransmitter synapse to mediate retrograde
signaling. They do possess all other characteristics of neurotransmitters including selective receptors.
Endocannabinoids are lipid-based neurotransmitters and provide retrograde feedback.
IONOTROPIC METABOTROPIC (GPCR)
ACETYLCHOLINE Nicotinic AChR Muscarinic AChR
GLUTAMATE AMPA, NMDA, kainate mGluRs
GABA GABA-A GABA-B
MONOAMINES Serotonin receptors All others are GPCR
NEUROENDOCRINE
