Lecture 3 Flashcards
What is the lizard: a case of PD?
• Loss of DA neurons in SN
• Knowledge of DA transmission integral for Treatment development
– L-dopa
• Symptom loss
• Doesn’t stop disease progressionWhat is resting membrane potential?
• Neuron at rest
– Unstimulated/inactive
• Membrane lipid bilayer
– Ions cannot easily cross
• Positively or negatively charged particles
• Unequally distributed across membrane
• Membrane polarized
– Carrying a charge
– -70mV (inside of neuron is 70 mv less than outside)
• Difference in electrical charge inside and outside cell
How is membrane potential recorded?
• Intracellular electrode
– Microelectrode
• Extracellular electrodes
• Detect difference between inside and outside of cells
What was the giant squid motor neurons used for?
• Used in early studies of resting membrane potential stability
• Hodgkin and Huxley with Eccles won Nobel prize for uncovering ionic mechanism of action potentials
• .5mm diameter (humans is 0.015 mm)
– Large diameter allowed easy electrode insertion
• Terminateonmuscle
• Similar to other multipolar neurons
What is the ionic distribution at rest like?
• Sodium (Na+) higher outside
– Membrane extremely resists passage
• Enters by random motion
– Driven inside cell by electrostatic forces and concentration gradient
• Chloride (Cl-) higher outside
– Membrane slightly resists passage
– At equilibrium
• Potassium (K+) higher inside
– Membrane moderately resists passage
– Driven inside cell by electrostatic pressure
– Driven out by concentration gradient
• Negatively charged proteins inside
– Cannot cross membrane
What is random motion?
Random motion:
Passage of ions through ion channels
down concentration gradient when neuron at rest
How do ions maintain resting potential?
Homogenizing factors
- Concentration gradient
• Tend to equally distribute
• Move from high to low concentration
– Electrostatic pressure
• Like repels like
• Opposites attract
Non-homogenizing factors
– Passive (no energy requirement)
• Random motion
• Due to Selective permeability-ion channels
– At rest:Cl-and K+ PASS READILY
– Active (hi energy requirement)
• Sodium-potassium pumps; maintain stability of RMP in spite of random motion of Na and K down concentration gradients
• Ion distribution returned to rest despite random motion
What are sodium potassium pumps; discovered by H&H?
Active transporter
– Energy consuming
Continuously transfer 3Na+ out and 2K+ in
What are postsynaptic potentials?
• Create signals in neurons
• Neurotransmitters bind to postsynaptic cell
– Cause electrical change in post synaptic cell
• Excitatory neurotransmitter:
– Depolariza1on (increase ++++)
– Membrane potential less negative
– Excitatory post synaptic potential (EPSP)
» Increase likelihood of AP
• Inhibitory neurotransmitter
– Hyper-polarization (increase—)
– Membrane poten=al more negative
– Inhibitory post synaptic potential (IPSP)
» Decrease likelihood of AP
What are EPSP and IPSP?
• Rapidtransmission
– Instantaneous rate of
transmission
• Duration can be variable
– due to graded response
• Graded
– Amplitude proportional to
• Stronger stimuli produce bigger IPSP or EPSP
– Bigger ion influx
– Due to increased NT release or receptor signalling
– Transmit decrementally
• Passive spread from
synapse (dendrite or soma)
• Get weaker as travel (like sound through air)
signal intensity
– Cant travel far (2 mm max)What is an EPSP?
Graded response: amplitude of signal proportional to stimulus intensity
->bigger stimulation = bigger PSP
->larger +ion influx = larger EPSP
Sodium ion flow inward is responsible for the generation of an EPSP
What is an IPSP
Graded response: amplitude of signal proportional to stimulus intensity ->larger -ion influx = larger IPSP Chloride ion flow inward is usually responsible for the generation of an IPSP
What is the integration of PSP to generate AP?
• Adding or combining signals into one overall output (or inhibition of output)
– One EPSP will not suffice
– Need summation
• Net affect of synaptic activity
• Threshold of excitation at axon hillock (axon initial segment)
– Synapses closer to axon hillock have larger effect on firing due to decremental transmission of far away PSPs
• Many inhibitory inputs
• Some distal dendritic sites have
mechanisms to amplify their PSPs
• integration of inputs must result in about -65 mv at hillock for AP
What is spatial summation?
- Occurs at Axon initial segment (AIS)
- integration (of EPSP and IPSP) across post synaptic locations
- local EPSPs or IPSPs occurring simultaneously combine to form larger response (or cancel out to form weaker)
What is temporal summation?
- Integration across time on same synapse
- Rapid succession
- Ex. High frequency vs low frequency inputs
What are action potentials?
• Massive
• Momentary
• Reversal of membrane potential
– -70mV to +50 mV (in 1 msec)
• Does not degrade over space
– Due to voltage gated channel
• All-or-none
– Equal strength throughout
– Occur as long as threshold of activation reached
– Intensity not graded, but frequency increases with more stimulationHow do voltage gated sodium channels generate and propagate APs?
• AP=fire, spike
• Threshold for excitation reached by postsynaptic integration at AIS
– Depolarized to at least -65 mv
– Opens voltage-gated ion channels
• Fast reversal of membrane potential
– -70 mvà+50 mv
– 1 msec
• All-or-none/not graded
– Occur to full extent –or– not at all
– Does not change response based off stimulus
• Just frequency
How are APs produced and conducted?
Voltage gated ion channels
- Open or close in response to membrane potential
What do ions do in APs?
Threshold of excitation
– VG Sodium channels open (rising phase)
• Rush in: electrostatic AND concentration gradient
• Increases membrane potential +50 mv
• Closes vg channel
– VG K+ channels open
• Driven out: electrostatic and concentration gradient
– Membrane repolarized; and slightly hyperpolarized (refractory period)
» K channels close gradually
» Resting potential re-established by random motion of ions and sodium potassium pump.
What is a refractory period?
• Absolute
– brief (1msec) post initiation
– Impossible to initiate new AP
in same neuron
– Sodium channels inactivated
– Spreads down axon behind AP
• Prevent backwards movements of AP
– Backwards propogating APs into soma and dendrites from axon hillock
• Limits to firing rate to 1000x per sec max
– Firing rate determined by stimulation intensity (of PSPs)
• Relative
– Follows absolute period
– Requires larger than threshold stimulus to initiate new AP
– More intense stimulation increase firing rate
What is axon conduction of action potentials?
• Active and passive
– Requires energy
• Nondecremental
– Just as strong from beginning (axon
hillock) to end (synaptic terminal)
• Row of voltage-gated sodium channels
– Domino effect
– Tightly packed
• Creates waves of depolarization
– Spreading can occur in either
direction
• Anterograde: hillock -> boutons
– Orthodromic conduction
• Retrograde: boutons -> hillock
– Antidromic conductionWhat is conduction in myelinated axons?
• Instant conduction along myelin=faster
– Ion flow only at nodes
• Saltatory conduction
– Ap jumps node to node
– Requires less energy
– Sodium channels only on nodes
• Passive (rapid and decremental) node to node
– Diminished before next node
• enough to open next node VG- Na+ channel
What is the velocity of axonal conduction?
• Faster in large diameter
– Less friction
• Faster in myelinated
• Large & myelinated really fast
– Large motor neurons • 224 MPH (100 m/s)
– VS 1 m/sec IN UNMYELINATED
– VS 25 m/sec IN UNMYELINATED SQUID GIANT MOTOR AXONS
• 100 m/sec in cats; 60 m/ sec in humans
PSP vs AP
EPSPs/IPSPs
• Decremental over space and time
• Fast
• Passive (energy is not used)
Action Potentials
• Nondecremental
• Conducted more slowly than PSPs
• Passive and active (use ATP)
What are interneuron APs?
• Not well understood • Conduction is Passive and decremental • Function to integrate neural activity in brain structure – Visual cortex • No axons • No AP • Small
What is the difference between cerebral neurons vs squid motor neurons?
• Hodkin-Huxley model based of squid neurons
– Not all cerebral neurons behave the same way
• More complex than model motor neurons
• Some cerebral neurons:
– Fire AP continually without
input
– Axons actively conduct graded signals and AP
– AP duration, frequency and amplitude different across neuron types
– Do not display AP
– Dendrites can conduct AP
• Comparison with motor neurons with caution
What are synaptic contacts?
• Axodendritic
– Axon ->dendrite
– Most common
• Axosomatic
– Axon->soma
• Axoaxonic
– Axon -> axon
– Mediate presynaptic inhibition or facilitation
• Selectively influence synapse rather than entire neuron
• Dendrodendrtic
– Dendrite -> dendrite
– Reciprocal
• Can be transmitted in either direction
• Dendroaxonic
– Dendrite -> axon
• Directed synapse
– Site of NT release close to post synaptic
contact
– Most common
• Undirected synapse
– Site of release and contact far
– Varicosities
• String of beads
– Common for monoamines (NE, DA)
– Neuroendocrine system releases neurohormones into blood streamWhat are dendrites?
Shaft
Spine
What is the chemical transmission of signals?
1. 2. 3. 4. 5.
• Neurotransmitter molecules
• Early studies on NMJ
– Muscles large
– Muscles only receive one synapse
– Acetylcholine (Ach)
1. AP reaches end of axon terminal 2. Calcium enters cell
3. Release NT into cleft (exocytosis)
4. NT binds receptors
5. Receptors influence post synaptic neurons
• Ion permeability (ionotropic)
– Create EPSP or IPSP
• Intracellular signalling (metabotropic)
– Longer lasting
6. NT degradation/recyclingWhat is small molecule neurotransmitter synthesis?
- Enzymatic conversion of amino acid precursors
* Presence of enzyme dictates which type of NT are released from cell
What are large molecule neurotransmitter synthesis?
Peptides
Processed by enzymes
What is neurotransmitter synthesis?
• Small molecule
– Classical neurotransmiPers
– Punctateeffects
– ReleaseinpulseforeachAP
– Synthesized in cytoplasm and golgi apparatus of terminals
• monoamines: Vesicles stuffed with precursor amino acid and synthesizing enzymes enroute to terminal
– Released into cleft
• Large molecule
– Neuropeptides
– Released gradually in response to increases in AP
– Widespread effects
– Released into ECF, ventricles or bloodstream
– Neuromodulators
– Synthesized in cell body, packaged in vesicles and then transported to terminal
What is neurotransmitter packaging?
• Secretory vesicles
– Proteins synthesized in RER
– Transported to golgi
– Bud off golgi to form vesicle
– Fast antergrade axonal transport
– Transporter proteins actively pump NTs into vesicles
• Example: VAchT
• Small clear core vesicles
– Contain small molelcule NT
– 40-60nm DIAMETER
• Large dense core vesicles
– Contain neuropeptides
– 90-250nmdiameter
• Coexistence
– More than one type of NT synthesized and released in neuron
• Normally mix of small and large NTHow are neurotransmitters transported?
• Anterograde to axon terminal
– Motor proteins
• Kinesin
– Uses series of attachment detachment steps
– Microtubule highway system
• Colchicine and vinblastine disrupt MT and prevent transport
– Requires energy
– Requires calcium
– Speed of transport is 0.5-1.5 cm/hrHow are neurotransmitters released?
- AP in axon terminal
- Open voltage gated Ca++ channels
– Clustered in active zone - Increase calcium influx
- Activates proteins responsible for
– Mobilizing vesicles
• Synapsin removes vesicles from mt network
– Fusing vesicles with synaptic membrane
• Synaptotagmin
• Snap25
• Syntaxin - Vesicles move to active zone
- Vesicles dock onto synaptic membrane
- Fuse with synaptic membrane and release NTs into cles
– Exocytosis
What is vesicle recapture?
• Local resynthesis of synaptic vesicles
• Pit formation
– Kiss and run
hypothesis
• Direct recycling
• Clatharin coating
– Endocytosis
– Cycle through endosomal compartment
– Indirect recyclingWhat are neurotransmitter receptors?
• Pre and post synaptic cell
• Specific for neurotransmitter
– Multiple receptor subtypes for each NT
• NT act differently in different areas of brain
• Distribution varies across CNS
– NT can only influence cells with receptors
– Ligand = molecule specific to receptor
• Example: Ach is a ligand for Ach receptor
What are inotropic receptors?
• Ligand–gated ion channels
– NT can open or close ion channel
• Influx or blockade of of sodium, chloride, potassium, or calcium
• Fast acting
• Generate EPSP or
IPSP
• Found postWhat are metabotropic receptors?
• 7 TMD
• G protein coupled
– Second messenger signalling
• Change gene expression
• Modify existing proteins
• Open or close ion channels
– Indirectly induce IPSP or EPSP
• Slow acting
• Long lasting changes
• More varied and diffuse effects
• More prevalent than ionotropic
• All neuropeptide receptors are metabotropic
• Found pre and post synaptically
– Presynaptic inhibition/ facilitationHow are neurotransmitter receptors activated?
• EPSP OR IPSP (ionotropic)
– Summated to initiate or inhibit AP generation in post synaptic cell
• Activate second messenger systems (metabotropic)
– 1st messenger=NT
– 2ND Messenger= Calcium, DAG, IP3, cyclic AMP (cAMP)
• Initiate intracellular cascades
• Open other ion channels
• Long lasting changes in:
– Synapse structure
– Gene expression
» Think effects of
epigenetics
– Cell survivalWhat are auto receptors?
• Metabotropic • Bind to own neuron’s NT • Presynaptic • Provide feedback – Reduce release when NT high – Increase release when NT low
What is neurotransmitter reuptake?
• Transporters on cell neurons and/or glia pick up NT from synaptic cles
– In the cell:
• NTs are repackaged into
vesicles for future release
• NTs are degraded by enzymes intracellularly
– Excreted
» Monoamines
– Used as precursors for NT synthesis
» Glutamate/GABA
– Used as precursors for energy
production
» GlutamateWhat is neurotransmitter degradation?
• Some NTs do not have transporters for reuptake
– Enzymes degraded in cleft
• Acetylcholine
– Acetylcholinesterase
» Inhibitors: pesticides, nerve gases venoms, reversible inhibitors used for treating ad
• Some NTs are taken back up into cell but degraded in cytosol
– Dopamine
• Mao
What is neurotransmitter recycling?
- NT reuptake can provide more NT to be repackaged and released immediately
- Some NT s can be broken down to form more of the same NT or used as a precursor to form different NT
What do glia do in synaptic transmission?
Astrocytes
– Domains
• Even distribution
• Little overlap of astrocytes
• Coordinate activity of synapses in domain
• 40K processes=high potential to regulate
– Modulate neuronal activity
• Have NT receptors
• Release NT
– Tripartite synapse
• Presynaptic, post synaptic and
astrocyte cell
– Uptake glutamate
• Reduce excitotoxicity
• Stimulate energy provision to neuron
– Support ongoing neuronal activityHow do glial communicate via gap junctions?
• Made up of connexin – Mutations and disease • Connect cytoplasm of 2 adjacent cells – Second messengers – Electrical signals • Electrical synapse – Faster than chemical synapse • also found in interneurons • Function to synchronize activities of similar cells – interneurons
What are amino acid transmitters?
• Small molecule
• Fast acting directed
synapses
• Byproducts of intermediary metabolism
What are excitatory amino acid NT?
• Carry 2 negative charges
• Dendrite major receiving area
– Require a lot of input for excitation
• Glutamate
– Most prevalent in CNS
– Ionotropic
• Sodium, potassium, and
calcium
– Metabotropic
• Gs and Gq
• Aspartate
• Generate EPSPWhat are inhibitory amino acid NTs?
• Inhibitory
– Carry one negative charge
– Soma major receiving area
• Require less input for inhibition
– GABA
• Synthesized from glutamate
• Most prevalent inhibitory NT in CNS
• Interneurons
• Ionotropic
– Chloride influx or potassium efflux
• Metabotropic
– Gi/o
– Glycine
• Mainly in spinal cord
• Ionotropic receptor
– Chloride ions
– Generate IPSP
• Can generate EPSP in certain conditionsWhat is the difference between glutamate vs gaba?
• Excitation vs inhibition • Yin and yang • Epilepsy – Too much glutamate – Not enough GABA • Learning and memory – Wire together fire together – Too much GABA or not enough glutamate impairs memory
What are monoamine neurotransmitters?
• AKA biogenic amines • MAO degrades • Catecholamines – Dopamine(DA) – Norepinephrine(NE) – Epinephrine (adrenalin) (EPI) – Precursortyrosine • Indolamines – Serotonin (5-HT) – Melatonin – Precursortryptophan • Histamines • Diffused effects – Metabotropic receptors – Released by varocosities • Psychotropic drugs mimic or affect these systems
What are catecholamines?
• Modulators in PNS and CNS • Several receptor subtypes • EPI only released in PNS – Sympathetic nervous system • Fight or flight • Increase energy availability • NE and DA found in both PNS and CNS – Cant cross BBB – Stay and made in CNS/PNS
What is catecholamine distribution in the brain
• NE
- Locus coereleus
-Stress/anxiety
-Vigilance
-NE enzymes only in NE neurons
• DA restricted distribution
- Nigrostriatal system
• Movement and reward
- Dorsal mesostriatal pathway
• Movement intiation
– Parkinson’s disease
- Ventral nigrostriatal pathway
• Positive incentive/reward
Mesolimbic cortical
• Projects to limbic structures
• Role in schizophrenia
- Periventricular
• Originate in hypothalamus
– Motivated behaviours hunger, thirst and sex
-Tuberalhypophyseal
• Lactation
-DA neurons do not have enzymes to further convert to NE or EPIWhat are indolamines?
• Serotonin (5HT)
– Modulatory
– Several receptor subtypes
– Distributed in 2 clusters
• Raphe nuclei
– Provide 80% of 5HT to forebrain
• Caudal system
– Sensory and motor function in spinal cord
– Appetite, sleep and aggression
• Decreased 5-HT increases
aggression
• High 5ht decreases carbohydrate appetite
• Decreased 5-ht = insomnia
– LSDWhat is indolamines (melatonin)?
– Fluctuates with light cycle
• Signals seasonal day length
– Regulate circadian rhythms
– Secreted in darkness
• TV, laptop, cellphones at
night?
– Cause drowsiness/sleep
• Used as sleep aidWhat is acetylcholine (ACH)?
• First identified in NMJ
– Botox
– curare
• Modulatory
– Several receptor subtypes
• Different CNS and PNS distributions
• Nicotinic
– Motor
– Curare
• Muscarinic
– In ANS
– atropine
• Simple synthesis and
degradation
– Unique synaptic degradation (AchE)
– Easy synthesis acetate+choline (ChAT)
• Role in learning and memory
– Alzheimer’s disease
– Dietary choline
– Atropine (mAchR antagonist)What are unconventional neurotransmitters (soluble gas)?
• Soluble gases
– Nitric oxide (NO)
– Carbon monoxide (CO)
– Both synthesized in neural cytoplasm
– Retrograde transmission
– Rapid diffusion to ECF
• Cross membranes
• Stimulate second messenger production
– Difficult to study
• Rapid breakdown
• Exist for secondsWhat are unconventional neurotransmitters (endocanninoids)?
- Receptors highly distributed – Anadimide • Sanskrit for “eternal bliss” – Pain reduction – Increase appetite – FaPy acids cross membranes – Retrograde transmission
What are neuropeptides?
Actions depend on amino acids, sequence
Loosely grouped: pituitary, hypothalamus, brain-gut, opiod, misc
Drugs and synaptic transmissions?
Agnostic - mimic efforts of the neurotransmitter
Antagonists - blocks the effect of the neurotransmitter
Alter NT activity at any point in cycle
What is behavioural pharmacology?
• Influential lines of research
• Treatments for neurological or neuropathological disorders
– Anxiety
– Depression
– Schizophrenia
– Parkinson’s and Alzheimer’s disease
– Epilepsy
• Drugs target specific receptors for specific effects
• Drug discovery and endogenous agonist discovery give insight into brain mechanisms of pleasure and pain
– Opioids
What is drug addiction?
- Legal status irrelevant
- Ease of crossing BBB
- Habitual use of a drug despite consequences and efforts to stop
- Physical vs psychological dependence
- Rewarding brain stimulation and CPP
- Mesotelencephalic dopamine system
What are opioids?
• Endogenous – Endorphin and enkephalin • Exogenous – From opium poppy resin (morphine/ heroin) • Produce analgesia • Act in PAG, hypothalamus, limbic
