Midterm 2 Flashcards
what are the types of neuroglia?
- astrocytes - form BBB
- microglia - immune function
- ependymal cells
- oligodendria (CNS)
- Schwann cells (PNS)
- satellite cells
how do neuroglia differ from neurons?
- do not form synapses
- have only one type of projection
- are able to divide (glial cell precursors can differentiate)
- less electrically excitable
what does the peripheral nervous system consist of?
- sensory afferents
- somatic motor efferents (skeletal)
- autonomic efferents (cardiac, smooth)
what is grey matter? what is white matter?
- grey: inner part of spinal cord, contains neuronal cell bodies and dendrites
- white: outer part of spinal cord, contains axons of descending and ascending fibres
what is the dorsal column medial leminiscus?
- ascending tract (sensory)
- carries sensory input on fine touch, vibration, and proprioception ot the brain
- located on dorsal side of SC
- sacral, lumbar, thoracic, cervical (medial to lateral)
what is the spinothalamic pathway?
- ascending tract (sensory)
- carries sensory input on temperature, crude touch, and pain to the brain
- divided into lateral (from medial to lateral: cervical -> sacral) and anterior
what are the corticospinal tracts?
- descending pathways (motor)
- carry motor signals from the brain to the skeletal muscles to control movement
- pyramidal and extrapyramidal
- pyramidal divided into lateral (from medial to lateral: cervical -> sacral) and anterior
what are the functions of the CNS?
- gather and integrate info from PNS
- process and perceive info from PNS
- organize reflex and autonomic responses
- planning and executing voluntary movements
- higher functions like cognition, learning, and memory
what is the function of the cerebrum?
performs high-order functions, composed of specialized lobes where integration is devoted
what does the frontal lobe do?
control skeletal (voluntary) muscle movements
- coordinates information from other association areas
- controls some behaviours (PFC)
what does the temporal lobe do?
contains auditory cortex + auditory association area
- hearing
what does the occipital lobe do?
contains visual cortex + visual association area
- vision
what does the parietal lobe do?
contains primary somatosensory cortex + sensory association area
- sensory information from skin, musculoskeletal system, viscera, and taste buds
what is the purpose of association areas?
neural pathways extend from sensory areas to association areas, which integrate stimuli into perception (input goes to primary cortices, interpreted in association areas)
what is BA1-3? what is BA4?
- BA1-3 = sensory cortex
- BA4 = motor cortex
how is the cerebral cortex organized?
6-layered architecture
- superficial layers have connections with other cortical areas
- intermediate layers receive input from subcortical areas
- deep layers project to subcortical areas
- thickness of each layer varies around the cortex
what are cortical columns?
6-layered functional networks
- make up the basic processing module for the cortex
- different functions for each layer (ex. input vs output)
- size of each layer varies around the cortex (ex. sensory cortex will have bigger input layers)
what are cortical-subcortical loops?
information loops between the cortex and grey matter structures (thalamus and basal ganglia)
- thalamus: relay centre for sensory and motor info
- basal ganglia: movement processing
what structures make up the basal ganglia?
- putamen
- globus pallidus
- subthalamic nucleus
- caudate
what are examples of cortical-subcortical loops?
- motor circuit (motor coordination): sensorimotor and premotor cortex -> thalamus -> BG ->
- limbic circuit (emotion): limbic and paralimbic cortex, hippocampus, and amygdala -> thalamus -> BG ->
where do motor fibres crossover (i.e. where does the corticobulbar tract turn into the lateral corticospinal tract?)
medullary pyramids (decussation of pyramids)
how are autonomic fibres organized?
motor fibres are accompanied by sensory fibres (nerves are mixed)
what is a physiological example of mixed nerves?
with inflammation in the GI tract (ex. appendicitis), GI motility will decrease and patient will feel visceral pain (referred pain) that is poorly localized
- referred: pain felt in one location may be caused by damage in a different location
does afferent information reach consciousness?
no, ANS operates on a subcortical level
- involved in homeostatic regulation (heart rate, GI motility, etc.)
what neurotransmitters are involved in the ANS?
- glutamate (most common)
- ANGII
- CCK
- oxytocin
- somatostatin
how do autonomic reflex arcs differ from somatic?
ANS contains 2-neuron efferents
- presynaptic cell bodies in CNS, postsynaptic cell bodies in ganglia
what cranial nerves are part of the parasympathetic NS?
- III: oculomotor
- VII: facial
- IX: glossopharyngeal
- X: vagus
what are autonomic afferents called?
what type of fibres are preganglionic efferents? what type of fibres are postganglionic efferents? what are their conduction velocities?
- general visceral afferents (GVAs)
- preganglionic: type B fibres (3-15 m/s)
- postganglionic: type C fibres (0.5-2 m/s)
where are the preganglionic and postganglionic cell bodies in the sympathetic NS? what neurotransmitters do they use?
- preganglionic: thoracolumbar spinal cord; ACh
- postganglionic: peripheral ganglia (close to SC, far from target); NE
where are the preganglionic and postganglionic cell bodies in the parasympathetic NS? what neurotransmitters do they use?
- preganglionic: craniosacral spinal cord; ACh
- postganglionic: peripheral ganglia (near to or within the wall of the target organ); ACh
where do preganglionic efferent cells originate and how do they exit the spinal cord?
- concentrated in the lateral horn of SC
- exit SC via ventral root and enter the paravertebral ganglia at the same level
what happens to preganglionic efferents after the enter the paravertebral ganglia (chain of ganglia beside the SC)?
- some synapse there
- some give off collaterals that travel rostrally or caudally
- some pass through the ganglia and enter a splanchnic nerve to enter the prevertebral ganglia (within abdominal cavity)
what is a splanchnic nerve?
mixed nerve (motor and sensory) that innervate the viscera
- smooth muscles, glands, etc.
where are the cell bodies of presynaptic parasympathetic neurons situated?
- cranial nerves III, VII, IX, and X (brainstem)
- sacral spinal cord (S2-S4)
what is unique about the smooth muscle of blood vessels?
have only sympathetic innervation
what happens to ciliary muscle in response to sympathetic vs parasympathetic input?
SNS: a-adrenergic (NE)
- pupil dilation (mydriasis), enhances far vision
PNS: M3-muscarinic (ACh)
- pupillary constriction (miosis), enhances near vision
what happens to the heart in response to sympathetic vs parasympathetic input?
SNS: B1-adrenergic (NE)
- SA node and ventricles; increases HR and contractility
PNS: M2-muscarinic (ACh)
- decreased HR and contractility
what happens to the stomach and small intestine in response to sympathetic vs parasympathetic input?
SNS: a- and B2-adrenergic (NE)
- decreased motility, sphincter contraction, reduced secretions
PNS: M1-, M2-, and M3-muscarinic (ACh)
- increased motility, relaxation of sphincters, increased secretions
what happens to the lungs in response to sympathetic vs parasympathetic input?
SNS: B2-adrenergic (NE)
- bronchodilation, increased ventilation
PNS: M3-muscarinic (ACh)
- bronchoconstriction
what happens to the abdominal arterioles in response to sympathetic vs parasympathetic input?
SNS: a- and B2-adrenergic (NE)
- vasoconstriction; diversion of blood from the GI tract to muscles
PNS: M3-muscarinic (ACh)
- vasodilation
what happens to the salivary and lacrimal glands with parasympathetic stimulation? what happens to the bladder?
M3-muscarinic (ACh)
- increased secretion
M2- and M3-muscarinic (ACh)
- contraction, sphincter relaxation
how is the ANS controlled by the CNS? what regions regulate autonomic function?
- firing of ANS preganglionic cells is determined by pathways that synapse onto them
- hypothalamus, preoptic and septal regions, lateral hypothalamus
- important for temperature regulation, food/water intake
what does cooling do to the body? what does heating do to the body?
- cooling: causes shivering, piloerection (goosebumps), increase in thyroid activity
- heating: reduces thyroid activity, sweating, and vasodilation
what happens when there are lesions to the heat loss centre (preoptic area/anterior hypothalamus)?
prevents sweating and cutaneous vasodilation, leads to hyperthermia (overheating)
what happens when there are lesions to the heat conservation centre (posterior hypothalamus)?
hypothermia
what is activated when blood glucose levels drop?
glucoreceptors in the hypothalamus
what happens when there are lesions to the lateral hypothalamus?
suppresses appetite/food intake (aphagia), potentially causing starvation and death
what happens when there are lesions to the ventromedial area (satiety centre)?
hyperphagia, potentially causing obesity
what causes Argyll Robertson Pupil?
caused by syphilis, which is caused by treponema pallidum (acts on the parasympathetic fibres of CN3
what are the stages of syphilis that eventually leads to ARP?
- primary: single sore; days-weeks
- secondary: rash over the body, hands, and feet; months
- tertiary: neurological, cardiovascular ARP; years-decades
what is the physiology behind ARP?
pupil fails to respond to light but accommodation reflex is normal
- optic fibres that project to the pretectal area of the midbrain are damaged (possibly due to bacteria in subarachnoid space) -> pretectal area projects to EN nucleus that gives rise to parasympathetic innervation of the eye that controls the pupillary reflex
what is the sympathetic input for micturition?
tonic
- pontine micturition centre (supraspinal) sends sympathetic preganglionic nerves from the lumbar spinal cord that synapse on postganglionic nerve -> hypogastric nerve
- input from the hypogastric nerve inhibits detrusor (muscle lining wall of bladder) through B-adrenergic receptors and excites the internal sphincter through a-adrenergic receptors
what is the parasympathetic input for micturition?
- pelvic nerve contains visceral afferent innervation of the detrusor and sends it to the pontine micturition centre
- pontine micturition centre sends descending commands to the sacral spinal cord via the reticulospinal pathway
- pelvic nerve travels from sacral SC to excite the detrusor muscle and inhibit the internal sphincter
- pudendal nerve travels from sacral SC to excite the external sphincter (striated muscle) through voluntary contraction
how are biological membranes like a circuit?
- capacitor: plates correspond to inner and outer faces of the membrane
- variable resistance (inverse of conductance; g): corresponds to gated ion channels shown with a switch
- electromotive forces: separation of charged ions across the cell membrane, set up by Na+/K+-ATPase
what kind of properties do molecules need to have in order to cross the membrane without a channel?
- small
- lipophilic
- uncharged
how are ion channels structured?
transmembrane proteins with a single pore
- some are multimers of homomeric or heteromeric subunits (HCN, Kv)
- some are monomers with repeating TM subunits
how are Nav and Cav structured?
pores are formed by monomers with 4 repeating 6-TM spanning regions
what are properties of selective ion channel structure?
- TM protein segments arranged around a central pore
- selectivity filter that regulates which ions can permeate the pore
- gate that can be opened or closed (some have more than one gate)
- voltage-gated channels have a voltage sensor
- ligand-gated channels have an intracellular or extracellular ligand binding site
- some have binding sites for intracellular proteins or second messengers
what are the phases of gating of the Nav channel?
involves 2 gates: activation and inactivation (ball and chain)
- depolarization to threshold opens the activation gate
- inactivation gate then closes, halting ion flow
- inactivation cannot be opened until the membrane repolarizes
what are the primary mechanisms that establish the RMP?
- Na+/K+-ATPase
- K+ leak channels
- resting permeability to Na+ and Cl- (not much)
- RMP ~ -70 mV
what are the concentrations and permeability of K+?
- ECF: 5 mM
- ICF: 150 mM
- P: 1
what are the concentrations and permeability of Na+?
- ECF: 145 mM
- ICF: 15 mM
- P: 0.03
what are the concentrations and permeability of Cl-?
- ECF: 100 mM
- ICF: 25 mM
- P: 0.1
what are the concentrations and permeability of Ca2+?
- ECF: 1 mM
- ICF: 10^-7 mM
- P: 0
what is the electrochemical driving force of an ion?
the difference between the membrane potential and the eqm potential of a given ion (Vm-Eion)
for a positive ion, what happens when Vm-Eion>0?
ion flows outward
for a positive ion, what happens when Vm-Eion<0?
ion flows inward
for a positive ion, what happens when Vm-Eion=0?
ion flow stops
what is the Nernst equation?
Eion=61/z log ([ion]out/[ion]in)
- predicts the equilibrium potential of a given ion
what is the GHK equation?
what is it hoe?
- predicts membrane potential using multiple ions
what is Ohm’s Law?
V=IR; V=I/g; I=gV
- resistance is the inverse of conductance
- a stimulus (change in current) will cause a resulting change in the membrane potential (voltage)
what can a stimulus (current) be a result of?
- input from another neuron (at synapses)
- can be caused by passive (graded) potential or active (action) potential
- can be spontaneous (ex. in pacemaker cells)
- electrophysiological studies
what 3 passive properties are important in neurons? what do they determine
determine how far a passive (graded) potential generated in a dendrite will travel, and whether a passive potential will result in an AP at the axon hillock
- membrane capacitance
- membrane (input) resistance
- intracellular longitudinal (axial) resistance along axons and dendrites
what do Rm and Cm determine? what does Rm also determine?
- Rm and Cm determine the shape and magnitude of a voltage response
- Rm also predicts how likely a small applied current is to generate an appreciable voltage response
how is the instantaneous current response not observed in voltage response?
voltage responses evoked by depolarizing and hyperpolarizing responses are rounded
why is voltage change not instantaneous like current change?
- capacitance makes voltage change lag
- in order for membrane depolarization to occur, injected charges need to cause rearrangement of charges at the membrane -> the higher the capacitance of the membrane, the longer this will take (capacitance is inverse of voltage)
what is the length constant?
- length constant = the distance from the site of current injection where the voltage response is 1/e of its original amplitude
- length constant = sqrt (Rm/Ra)
- the higher the ratio of Rm to Ra, the lower the loss of current and the greater the length constant
how does increasing diameter affect Rm, Ra, and the length constant?
- decreases Rm (more ion channels)
- decreases Ra much more
- increased length constant
how are changes in Vm measured?
using an internal electrode and an extracellular reference electrode
when do slower Kv channels open in an AP?
-20 mV
what happens to Nav channels at 30 mV?
they become inactivated
what properties ensure that AP propagation is unidirectional?
- Nav inactivation
- increased Pk
where does synaptic integration occur? what properties does this location have?
axon hillock
- high density of Nav channels -> lowest threshold for spike initiation
what is temporal summation? what is spatial summation?
- temporal: successive stimulations at the same location (same input source)
- spatial: successive stimulations at different locations (different input sources)
what is the shunting effect?
when summation doesn’t produce a greatly additive effect
- could be due to other factors (ex. cell resistance) reducing the expected summation
what is an excitatory postsynaptic potential (EPSP)?
transient depolarization of postsynaptic neuron due to increased conductance of the postsynaptic membrane to Na+/K+ in response to NT binding
- at RMP, driving force for Na+ to enter the cell is greater than for K+ to leave, resulting in depolarization
what is an inhibitory postsynaptic potential (IPSP)?
transient hyperpolarization of postsynaptic neuron due to (most often) increased Cl- conductance of postsynaptic membrane in response to NT binding
- Cl- enters the cell at RMP causing hyperpolarization
what is saltatory conduction?
when an AP jumps from node to node due to myelination
in what axons is conduction the fastest?
large, myelinated axons
- greater diameter reduces axial resistance
how do active and passive potentials change with distance?
- active: AP magnitude and duration is constant; delay between stimulus and response increases with distance
- passive: graded potential magnitude decreases with distance
why are APs regenerated at Nodes of Ranvier?
- membrane conductance is high
- membrane resistance is low (due to channels and no myelin)
- Nav and Kv density is high
why do passive potentials propagate rapidly between nodes?
- membrane resistance is high (no channels, lots of myelin)
- membrane capacitance is low (capacitance is difference in charge between plates; if plates are farther apart due to myelin, capacitance decreases)
how do you improve conduction in axons?
- increase diameter of axon (decreases axial resistance -> increases conduction velocity)
- myelinate the axon (increases membrane resistance)
what makes myelin in the CNS? PNS?
- CNS: oligodendrocytes
- PNS: Schwann cells
what is multiple sclerosis? what is a conduction block? what is a frequency-related block?
a disease of myelination in the CNS
- immune attack causes demyelination
- conduction block: Nav channel density gets too low, terminating the AP
- frequency-related block: conduction still occurring but decreases in frequency at each node
what is cross-talk between demyelinated axons?
AP in one axon terminates and continues in another axon
what events lead up to synaptic transmission?
- input received from dendrites is passively propagated to the hillock
- input can be excitatory or inhibitory, summation occurs at hillock
- if summed signal is subthreshold = no AP
- if summed signal is suprathreshold = AP occurs and propagates down axon
what are the different types of NTs?
- small molecule (glutamate (primary excitatory NT), GABA, ACh)
- gaseous (NO)
- amines (DA, NE, 5-HT)
what determines the action of a NT?
the receptor it binds to
where does ACh act? what receptors does it act on?
- PNS: at NMJ and autonomic ganglia
- CNS: basal ganglia and SC
receptors: - nAChRs @ NMJ
- MAChRs at autonomic ganglia
what are the inhibitory NTs?
- GABA: inhibitory NT in the brain
- glycine: inhibitory NT in SC
what is DA used for? what about 5-HT?
DA: motivation, motor function, reward and pleasure
- 5-HT: mood, appetite, sleep
how do ionotropic receptors act? what responses do they produce? what are some examples?
action:
1) NT binds
2) conformational change results in channel (pore) opening
3) ions flow across membrane
- fast EPSPs and IPSPs
examples:
- CNS: ionotropic glutamate receptors (NMDA, AMPA, iGluR in retina), GABAa, GABAc
- NMJ: nAChRs
how do metabotropic receptors act? what responses do they produce? what are some examples?
action:
1) NT binds
2) G protein activated
3) G protein subunits or intracellular messengers modulate ion channels
4) ion channel opens
5) ions flow across membrane
- slower responses
examples:
- CNS: metabotropic glutamate receptors (mGluR), GABAb
- PNS: MAChRs
what is the reversal potential of an EPSP?
the potential at which the net direction of ion flux reverses
- when the Na+ influx exactly offsets the K+ efflux (0 net current/ion flow)
what is happens when Eion is reached?
when the electrical gradient and concentration gradient of an ion are balanced, causing no net movement of THAT ION across the membrane
how can you experimentally determine the reversal potential for an EPSP?
ex) a dendrite held at a varying voltages (voltage clamp) while applying a fixed EPSC to elicit a constant EPSP
- single channel current recording using patch clamp
- ex) at -102mV, an EPSP will display a greater Na+ influx and K+ will also move inward b/c the Vm is more (-) than Ek
- ex) at -32mV, an EPSP will display K+ efflux and weaker Na+ influx since it is closer to ENa than -102mV (also farther away from Ek so greater drive for K+ to move)
what is an excitatory postsynaptic current (EPSC)?
currents that are applied to elicit an EPSP
- active (ionotropic channels opening and closing)
how are extracellular signals converted into intracellular events?
signal transduction: the transmission of an extracellular stimulus to an intracellular signal via specific membrane receptors
what are properties of ligand-gated channels?
- can be directly or indirectly gated
- often non-specific (permeable to Na+ and K+, sometimes Ca2+)
- heteromeric, vary in subunit composition (generally, 5 subunits, each with 4-TM spanning helices)
what is an example of direct gating?
NT binding to the ionotropic receptor
- nAChR directly binding ACh
what is an example of indirect gating?
NT downstream binding to an ion channel by directly binding a GPCR
- MAChR binding ACh, G protein subunit activates K+ channel
what is the structure of metabotropic receptors?
7 TM spanning helices, extracellular ligand binding site, intracellular G protein binding site
- helices surround central aqueous pocket containing ligand binding site
what is the process of G protein activation?
- ligand binding to the GPCR leads to activation of the G protein by switching it from GDP bound (inactive) to GTP bound (active)
- a subunit dissociates from By subunit, both can go on to activate intracellular effector molecules
- effector activation leads to second messenger molecules (cAMP, Ca2+) that have other cellular effects (opening/closing ion channels, regulating gene expression)
what is presynaptic modulation?
presynaptic neuron second messengers can modulate the activity of K+ and Ca2+ channels + NT release to regulate the efficacy of NT release -> affects the size of the postsynaptic potential
what is postsynaptic modulation?
postsynaptic neuron second messengers can directly alter the amplitude of postsynaptic potentials by modulating ionotropic receptors
what is the Gs pathway?
- E/NE binds to B1-adrenergic receptor
- activates alpha(s) subunit, which activates adenylyl cyclase (AC)
- AC converts ATP to cAMP
- cAMP activates protein kinase A (PKA)
- net effect = upregulated activity of voltage-gated HCN channels, speeding up heart rate
what is the Gi pathway?
opposite of Gs, inhibits AC
- slows down heart rate
what is the Gt pathway?
- light photoactivates rhodopsin, causing the dissociation of alpha(t) (transducin) from By
- transducin activates phosphodiesterase (PDE)
- PDE breaks down cGMP to GMP, decreasing cGMP levels
- decreased cGMP levels closes CNG channels that are normally open in the dark, hyperpolarizing the cell and reducing glutamate release
what is the Gq pathway?
- ACh binds to M1-muscarinic receptors in smooth muscle surrounding the bronchi, causing the dissociation of alpha(q) from By
- alpha(q) activates phospholipase C (PLC)
- PLC converts PIP2 (in the membrane) to IP3, acting on IP3 receptors on the ER membrane
- causes Ca2+ release from ER, causing smooth muscle contraction and bronchoconstriction
- PLC also converts PIP2 -> DAG
- DAG activates protein kinase C (PKC)
what equipment is used in electrophysiological measurements?
- intracellular electrode: applies current/voltage commands
- extracellular electrode: reference
what does in vivo mean? what does in vitro mean?
- in vivo: as a whole animal
- in vitro: specific neurons, cells, etc.
what are voltage clamps? what are they used for?
the experimenter specifies a voltage and measures the resulting current; useful for:
- study single channels or one specific type of channel
- investigate which ions the channel is permeable to or the speed of opening and closing
- testing if a particular chemical or substance alters the channel
what are current clamps? what are they used for?
the experimenter injects current and measures the resulting changes in membrane potential (voltage, usually APS); useful for:
- study excitable cells like neurons
- find out which ions are important for APs
- test if a drug blocks APs
what are patch clamps? what are they used for?
form a tight (high-resistance) seal between a glass micropipette containing an electrode and the plasma membrane of a cell
- allows experimenter to control the extracellular and intracellular composition
what are the types of patch clamp configurations?
- cell-attached recording: tight contact between pipette and membrane
- inside-out recording: single channel recording, can modify intracellular/cytoplasmic domain
- whole-cell recording: cytoplasm is continuous with pipette interior
- outside-out recording: extracellular domain is accessible (can test the actions of NTs, etc.)
how can current be measured?
- through individual channels (single channel/microscopic current)
- through numerous channels (macroscopic current)
- average of microscopic currents display the macroscopic current*
what is the convention for current recordings?
positive current entering the cell presents as downward deflections
what are the advantages and disadvantages of in vivo?
advantages:
- real-time recording in live animals
- high physiological relevance
disadvantages:
- technically difficult
- little to no control of intracellular or extracellular fluids
what are the advantages and disadvantages of in vitro?
advantages:
- isolated tissues or cells are easier to work with
- control over solutions
disadvantages:
- less physiologically relevant
- molecular techniques required
what are the advantages and disadvantages of heterologous expression?
advantages:
- higher expression levels result in larger currents
- control over solution composition
- ability to modify channel structure
disadvantages:
- endogenous channels may interfere with recordings
- less physiological relevance
what is defined by the slope of the I-V curve? what does an I-V curve look like in the absence of a concentration gradient?
- conductance (y)
- linear (m=y)
what is Hebb’s rule? what does Hebbian plasticity entail?
neurons that fire together, wire together
- learning and memory can occur due to the changes in strength of connections between neurons; can lead to:
- LTP
- LTD
what is homeostatic plasticity?
moves neurons back to their original state (set point/baseline) after modification -> in terms of firing (ex. temporarily increased input/firing returning back to baseline)
- ex. after potentiation
what is potentiation (facilitation)?
with higher frequency/increased stimulation, greater passive potentials are elicited (ex. EPSP will change in size based on frequency of input)
- no summation
what is the trisynaptic circuit of the hippocampus?
circuit with high degree of potentiation
- preforant path (from entorhinal cortex) synapses onto granule cell in dentate gyrus -> granule cell synapses onto CA3 pyramidal cell -> Schaffer collaterals synapse on CA1 pyramidal cells
what are Schaffer collaterals?
axons that travel from CA3 to CA1 (axons of CA3 pyramidal neurons)
- synapse on CA1 most studied area of LTP
what is long-term potentiation (LTP)?
a process whereby synaptic activity increases future postsynaptic potentials
what is the favoured mechanism of LTP?
AMPAR and NMDAR (glutamate receptors permeable to Na+ and K+; NMDAR additionally permeable to Ca2+)
- at RMP, NMDAR are blocked by Mg2+
- Ca2+ influx through NMDAR activates intracellular CaMKII pathway
- causes insertion of AMPAR on postsynaptic membrane from vesicles
what are the properties of AMPARs?
- permeable to Na+ and K+
- tetrameric (GluA1-4)
- central Arg provides specificity
- inward current at -mV, outward current at +mV
- without GluA2, inwardly rectifying
what are the properties of NMDARs?
- blocked by Mg2+ at RMP
- depolarization dispels Mg2+
- permeable to Na+, K+, and Ca2+
what are the postsynaptic events that cause LTP?
high activation:
- high amounts of glutamate binds to AMPARs on postsynaptic membrane, depolarizing the membrane
- adjacent NMDARs become depolarized, removing Mg2+ block and bind glutamate, allowing Ca2+ influx
- activates CaMKII pathway, phosphorylating AMPARs and causing exocytosis of AMPARs from vesicles
- net result: greater expression of AMPARs on postsynaptic membrane
what are the postsynaptic events that cause LTD?
weak activation:
- low amounts of glutamate bind AMPARs on postsynaptic membrane, depolarizing the membrane
- adjacent NMDARs become depolarized, removing Mg2+ block and bind glutamate, allowing Ca2+ influx
- activates PP2B (calcineurin) and PP1 (protein phosphatase 1) pathway, causing dephosphorylation of AMPARs and causing endocytosis of AMPARs into vesicles
- net result: lower expression of AMPARs on postsynaptic membrane
what is the hippocampus? what does bilateral loss of the hippocampi result in?
- medial temporal lobe structure with well characterized regions and connections critical for long-term memories
- loss will produce anterograde amnesia, or inability to form new memories
what are the 4 major structures that form the hippocampal LTP circuit?
1) CA1: major output goes to layer V of entorhinal cortex (EC)
2) CA3: receives input from dentate gyrus (DG) and EC
3) DG: projects to CA3 and receives input from EC
4) EC: interface between hippocampus and cortex
where is LTP observed in the hippocampal circuit? what principles are present?
repeated stimulation of EC cells that project to DG leads to increased EPSPs in DG overtime
- only the activated set of synapses will be potentiated (input specificity)
- enough presynaptic axons must fire coincidentally to activate the postsynaptic cell (cooperativity)
how does LTP present in dendritic spines?
enhanced receptors, more visible spines, changed configuration
how does fear learning move from local to distributed? what does this explain?
- 1 day after learning: most associations involve hippocampus
- 36 days after learning: connections involve cerebral cortex, thalamus
- explains why loss of hippocampus prevents new memories but old memories are preserved
how does brain plasticity contribute to recovery after surgery?
following traumatic injury, functional brain responses can be “remapped” through new groups of neurons being recruited (new connections are made and strengthened to compensate for those lost)
how are children brain connections different than teens/adults?
- children: connections are stronger between neurons that are anatomically close but functionally unrelated
- teens/adults: connections are stronger between neurons that are functionally related but distant
what does outward current look like on an IV plot?
positive
what are the early and late stages of LTP?
- early: insertion of receptors from vesicle stores
- late: modification of gene expression and structural changes
are LTD and LTP dictated by presynaptic or postsynaptic mechanisms?
postsynaptic
what are “silent” synapses?
synapses that contain only NMDARs
- can be woken up by LTP protocols that cause insertion of AMPARs on the membrane
what is the mechanism of presynaptic LTP?
repetitive synaptic activity leads to entry of presynaptic Ca2+ -> AC pathway -> increased cAMP -> protein kinase A (PKA) activation -> Rab3a and RIM1 (vesciular related proteins) -> exocytosis of more NT release
what is the mechanism of NMDAR LTD?
Ca2+ entry through NMDAR channels -> protein phosphatases calcineurin and protein phosphatase 1 (PP1) activate -> dephosphorylates AMPARs and triggers endocytosis of AMPARs
- happens spontaneously (no way of knowing when)
what is the mechanism of mGluR LTD?
mGluR triggers AMPAR postsynaptic internalization, a process that appears to require protein synthesis
what is the mechanism of endocannabinoid (eCB) LTD?
mGluR activation -> phospholipase C (PLC) and/or intracellular Ca2+ initiates the synthesis of eCB
- eCB travels in a retrograde manner to bind to presynaptic cannabinoid 1 receptors (CB1R) that depress NT release
how is LTP maintained (what late events occur)?
structural changes that maintain plasticity
- AMPARs are anchored by scaffolding protein groups including PSD95, cadherins and catenins
- involves changes in expression of levels of structural proteins at postsynaptic density (PSD)
what is the function of:
a) PSD95?
b) cadherins?
c) catenins?
a) PSD95: anchors NMDARs to cytoskeleton
b) cadherins: mediate adhesion through interactions across the synaptic membrane and associate with AMPARs
c) catenins: couple AMPARs to cytoskeleton
how does LTP and LTD occur with changes in structural proteins?
- LTP: cadherins are increasingly associated with synaptic membrane
- LTD: internalization of cadherins is required for removal of AMPARs
when is information stored?
when synapses that connect neurons become more (LTP) or less (LTD) able to fire in response to a particular stimulus
how are memories stored into STM?
at first in the hippocampus, where synapses between excitatory neurons start to form new circuits within seconds of the events to be remembered and increases in the strength of even a small number of synapses create a new circuit that stores a new memory (STM)
how does forgetting occur?
when release of NT does not produce EPSPs sufficient to reach threshold, the synapse becomes weaker and the circuit may disappear entirely
what is the experimental evidence that links LTP to learning and memory?
- in absence of LTP, learning and memory is substantially impaired
- LTP increased during fear conditioning
- memories can be inactivated and reactivated with LTD and LTP
what are hippocampal place cells? why are they significant?
- place cells: pyramidal neurons within the hippocampus
- single unit recordings from hippocampus show that specific place cells fire only when an animal is in a particular location
- through simultaneous exposure, place cells can fire in response to associated stimuli (foods, light, touch), providing a link to learning and memory
what are Purkinje cells? what kind of input do they receive?
- large GABAergic neurons that project to deep cerebellar nuclei (important for motor learning)
2 types of excitatory input: - powerful synaptic contact from a single climbing fibre (from inferior olive nucleus)
- synaptic input from ~150k parallel fibres, from the tiny granule cells of the cerebellum itself
when do parallel fibre synapses change their strength?
only if they are active at the same time as the climbing fibre
- EPSPs generated by the parallel fibres became smaller when both the parallel fibres and the climbing fibres were coactivated at low frequencies
what does the climbing fibre represent?
error signal (modifies motor movement)
- feedback mechanism
how is the climbing fibre and parallel fibres related to LTD?
parallel fibre EPSP amplitude decreases with climbing fibre stimulation
- parallel fibre activates motor movement, climbing fibre activated when movement is wrong, so LTD is used to unlearn that configuration of movement
what molecular events of the parallel fibre onto the Purkinje cell causes LTD?
glutamate released from parallel fibre binds mGluR on Purkinje cell dendritic spine -> activates PLC -> converts PIP2 to IP3 and DAG (IP3 causes Ca2+ release from ER which activates PKC; DAG directly activates PKC) -> PKC phosphorylates substrate proteins -> internalization of AMPARs
what molecular events of the climbing fibre onto the Purkinje cell causes LTD?
climbing fibre depolarizes Purkinje cell dendritic spine causing Ca2+ influx -> increased intracellular Ca2+ induces Ca2+ release from ER -> activates PKC -> PKC phosphorylates substrate proteins -> internalization of AMPARs
how is Alzheimer’s Disease related to synaptic plasticity?
- in AD, LTP is blocked and LTD is triggered (believed to underlie cognitive decline)
- associated with loss of plasticity
- AB oligomers bind to NMDARs/AMDARs causing their internalization; leads to thinning and loss of synapses (causing memory problems)
how is addiction related to synaptic plasticity?
- drugs of abuse (ex. cocaine) alter synaptic plasticity in the brain’s reward centre, leading to changes in behaviour
- associated with excessive plasticity
what are the molecular events relating plasticity and addiction?
- drugs of abuse modulate synaptic function and plasticity in the Ventral Tegmental Area (large part of reward system)
- cocaine, amph, ecstasy target DA transport, directly increasing DA
- other drugs target GABAergic neurons , inhibiting their activity and indirectly increasing DA
- others elicit LTP by increasing the AMPAR/NMDAR ratio at glutamatergic neurons (through mGluR)
- increase DA in VTA and projection areas
how are NMDARs affecting GABAergic neurons?
NMDAR on glutamatergic neurons cause Ca2+ influx and activate nitric oxide synthase (NOS) -> diffuses to GABAergic neurons and inhibits GC pathway, decreasing levels of cGMP
how is cocaine use related to structural proteins?
- normally, GluA1/2 AMPARs are present in synapses, making them impermeable to Ca2+
- cocaine use inserts cadherins which insert GluA1 homomers at synapse from vesicles (GluA1 is Ca2+ permeable)
