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Neurochemistry Flashcards

1
Q

Blood brain barrier (BBB)

A
  • Is different from the blood-CSF barrier, but both together maintain the CNS environment
  • BBB is dependent on tight junctions btwn endothelial cells in (non-fenestrated) capillaries within the CNS
  • Blood-CSF barrier is from tight junctions btwn ependymal epithelial cells in the choroid plexus
  • Some specific areas of the brain do not have a BBB for neurosecretory products to pass into circulation (posterior pituitary)
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2
Q

Other cells involved in BBB

A
  • Endothelial cell tight junctions create the BBB, are surrounded by basement membrane, astrocytes, and pericytes
  • Astrocytes dictate the endothelial cells to form these tight junctions (foot processes will completely surround the capillary)
  • Pericytes play a role in angiogenesis and communicate to other cells (one pericyte will be directly adjacent to the capillary)
  • Pericytes also are source of adult pluripotent stem cells
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3
Q

Developmental aspects of BBB

A
  • Tight junctions begin to form early during fetal development
  • Permeability to substances is greater in developing brain
  • Before 6 mos the brain is susceptible to hormones, neurotoxins, and other chemicals
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4
Q

Brain uptake index (BUI)

A
  • Relative uptake of a molecule as compare to deuterium water (DOD)
  • DOD BUI is arbitrarily set to 100%
  • Some substances (nicotine and alcohol) are over 100%, while most are under 100% (caffeine, heroine, ect)
  • The ability of a substance to pass through the BBB w/o aid of a transporter is based on its hydrophobicity
  • The more hydrophobic a substance, the more easily and quickly it will pass through the BBB
  • Mannitol is poorly permeable and is used to dehydrate the brain via osmosis to reduce swelling
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5
Q

Partition coefficient (PC)

A
  • The partition btwn an oil and aqueous phase, to predict the accumulation behind the BBB
  • The higher the PC (the more hydrophobic a substance), the greater the brain uptake
  • Gases (NO) and volatile anesthetics can rapidly diffuse into CNS
  • Glucose is taken up by facilitate transport mechanism, driven by concentration gradient but doesn’t require energy
  • GLUT transporters are on endothelial cells, ependymal (?) cells, astrocytes, microglia and neurons
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6
Q

General features of BBB

A
  • Enz barriers are found at the luminal side of the endothelial cells
  • Toxic materials can destroy the BBB: bordatella pertussis (whooping cough) toxin destroys tight junctions, LPS from GN cause neuro-inflammation and disrupts the BBB by elevating matrix metalloproteinases
  • Drug abuse may lead to permanent BBB damage
  • Aging and diabetic condition have profound negative effect on BBB
  • BBB dysfunction is observed in AD pts who also have HTN and CVD
  • Free bili in newborns is toxic as it can pass thru the BBB and be deposited in the brain
  • Bili levels increase when a mother develops Abs to the fetal Hb. Bili breakdown is stimulated by light
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7
Q

Formulations to penetrate BBB

A
  • Abs to transferrin receptors (TR) may sneak drugs through BBB
  • BBB contains many TRs that transport Fe-TF to the interstitium
  • If an Ab to the TR is made and linked to a drug, that drug could be transported across the BBB via the TR
  • CAMs are also upregulated in capillaries within the CNS at sites of inflammation/hypoxia
  • Therefore finding proteins that bind to CAMs and coupling them w/ certain drugs can carry those drugs to specific sites of inflammation
  • WBCs use these CAM markers to exit the blood and enter the CNS at times of inflammation/hypoxia
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8
Q

Electrical vs chemical synapse

A
  • Chemical synapse is the typical and most common synapse (using NTs)
  • Electrical synapse is directly passing current from one cell to another (gap junctions)
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9
Q

Steps of synaptic transmission

A
  • Presynaptic neuron depolarizes down to nerve terminal, causing an influx of Ca by voltage-gated Ca channels
  • Increase in [Ca] leads to fusion of synaptic vesicles w/ plasma membrane (botox interferes w/ this step), causing the NTs in those vesicles to be released into the synapse
  • NTs diffuse across and bind to postsynaptic cell at their receptors, causing a change in postsynaptic membrane conductance
  • This can either be excitatory (EPSP, depolarization) or inhibitory (IPSP, hyperpolarization), PSP= postsynaptic potential, in neurons
  • In muscles the depolarization of the motor-end plate is called end-plate potential (EPP)
  • If the depolarization is enough for Vm to reach threshold the postsynaptic cell will fire an action potential (AP)
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10
Q

Synaptic delay

A
  • Time btwn depolarization of presynaptic cell and initiation of postsynaptic response
  • Is the time required for release of NT from the presynaptic cell in response to the presynaptic AP
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11
Q

Neuromuscular junctions (NMJ) 1

A
  • A chemical synapse that results in EPP in the muscle cell (leading to contraction)
  • The NT acetylcholine (ACh) is released from the neuron onto the NMJ where it binds to the nicotinic ACh receptor (nAChR)
  • The other AChR is the muscarinic receptor (in the heart)
  • Normally gNa«gK, due to no movement of Na but loss of K from leaky channels, but conductance of both ions changes to gNa=gK upon ACh binding to AChR (both ions move thru the channel)
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12
Q

Neuromuscular junctions (NMJ) 2

A
  • When ACh binds to nAChR, the receptor opens its channel and lets Na in and K out, making gNa=gK
  • While both ions are moving in opposite directions, the overall increase in conductance of Na is greater than the increase in conductance of K so the Vm increases, closer to Ena (which is +60, as opposed to Ek which is -80)
  • This change in Vm is high enough to reach threshold (when gNa=gK depolarization occurs), thus beginning an AP along the membrane of the muscle, ultimately leading to contraction
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13
Q

Stopping EPPs

A
  • EPPs must be transient or else tetanus would occur
  • To stop EPPs, nzs called acetylcholinesterases are synthesized and present on the post junctional membrane
  • These rapidly breakdown the ACh
  • Some of the ACh diffuses out of the synaptic cleft
  • Inhibitors of these nzs are called anticholinesterases
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14
Q

nAChR structure

A
  • nAChRs at the NMJ are composed of 2A,B,D,E subunits
  • nAChRs in neurons are composed only of A and B subunits
  • nAChR formed from different subunit combinations vary in gating kinetics, single channel conductance, sensitivity to ACh, Ca permeability, and affinity for pharmacological drugs
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15
Q

Nicotine addiction

A
  • Nicotine minmics the NT ACh in the brain and stimulates dopaminergic neurons in the mesolimbic reward pathways
  • Desensitization occurs when the nAChRs enter a permanently closed state (at high nicotine or ACh concentrations) due to repetitive and prolonged binding
  • Desensitization leads to acute tolerance and subsequent receptor upregulation (to compensate for the desensitization)
  • Chronic nicotine use leads to multiple neuroadaptations that underlie nicotine withdrawal symptoms
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16
Q

Neuron-neuron synapses

A
  • Use many different NTs such as ACh, AAs (glutamate, glycine, aspartate, GABA), peptides (endorphins), amines (norepinephrine, DA, serotonin), lipophilic arachidonic acid (ADA) derivatives (cannabinoids)
  • Each neuron can innervate many different neurons and can be innervated by many other neurons
  • Synaptic transmission is terminated by breakdown of NT, reuptake of NT into glial cells or presynaptic neuron, and diffusion out of synapse
  • Cocaine inhibits reuptake of DA, and prozac inhibits reuptake of serotonin (both transport mechanisms are Na dependent)
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17
Q

NT receptors

A
  • All are either ionotropic (binding to the receptor opens a channel in the receptor and leads to ion movement) or metabotropic (receptor is GPCR and leads to activation of other channels and/or 2nd messengers)
  • EPSPs (increase in gNa, decrease in gK, or increase in both) from excitatory NTs: glutamate, aspartate
  • IPSPs (increase in gK or increase in gCl) from inhibitory NTs: GABA, glycine
  • EPSPs and IPSPs sum to determine the overall value of the Vm
  • Each synapse will depolarize or hyperpolarize the postsynaptic cell by 1-2mV
18
Q

Summation of synaptic inputs

A
  • Integration of many synaptic inputs arriving simultaneously from different presynaptic cells is spatial summation
  • Integration of a series of inputs from a single synaptic input occurring in rapid succession is temporal summation
  • Spatial summation inputs can cancel each other out if in opposite directions (EPSP+IPSP)
19
Q

Use-dependent changes in synaptic strength

A
  • The synaptic strength is not a fixed value
  • This is synaptic plasticity, which can result in potentiation (increase of a response to stimulation) or depression (decrease of a response to stimulation)
20
Q

Resting membrane potential

A
  • A net outward K current is responsible for the negative resting membrane potential, Vm (which is usually about -80mV as compared to the outside of the cell)
  • This outward K current is due to leaky K channels
  • In contrast, there is very little movement of Na into the cell
  • The NA/K ATPase is responsible for maintaining the concentration differences for both K and Na, by moving these two ions against their gradient (moves 3 Na out of the cell and 2 K into the cell)
21
Q

Equilibrium potential

A
  • The value of the membrane potential that is in equilibrium w/ a concentration difference
  • The equilibrium potential (E) can be calculated for an ion when it is at various concentrations in and out of the cell by the Nernst eqn
  • Combining the concentration gradient and the force on the ion by the Vm is the electrochemical potential of the ion
  • When these two factors cancel each other out, the ion is at E
  • When Vm=E, there is no net movement of the ion in or out of the cell
  • Ena= +70mV, Ek=-90mV
22
Q

Currents of ions and Ohm’s law

A
  • Ohm’s law is used to calculate how much current of an ion will be generated based on the conductance, Vm, and E of an ion
  • I=g(Vm-E); stating that the difference of the Vm and E for the ion times the conductance will give a value of current
  • Vm-E represents the driving force for ion movement (potential difference), and g (conductance) is the same as 1/R (inverse of resistance), since conductance is the ease at which ions flow)
  • The Vm-E for Na is 5x more than it is for K, but the gK is 100x more than gNa, thus in the resting state there is Ik>Ina (leading to Vm being close to Ek)
23
Q

Chord conductance eqn (CCE)

A
  • Conductance is directly proportional to the # of open ion channels
  • The CCE gives the Vm, by producing a weighted average of the equilibrium potentials (using the conductance ratio for each ion as the weighting factor)
  • Vm= (gK/gK+gNa)Ek + (gNa/gK+gNa)Ena
  • At resting state gK is 100x more than gNa and the Vm is very close to Ek (Vm=-80mV, Ek=-90mV)
  • During an AP the gNa greatly increases and drives the Vm toward Ena (depolarizing the cell)
  • During inhibition the gK further increases (or gCl increases) and this drives the Vm even closer to Ek and Ecl (both are about -90mV) causing hyperpolarizaiton
24
Q

Firing an AP 1

A
  • The usual threshold value of Vm for the firing of an AP (at the initial axon segment) is about -60mV
  • APs are due to successive opening of voltage-gated Na channels, starting at the initial axon segment (just adjacent to axon hillock)
  • Voltage-gated Na channels open upon depolarization of the membrane, leading to influx of Na (increases gNa) and further depolarization
25
Q

Firing an AP 2

A
  • Axon depolarizes up to 50mV, but never reaches the Ena of 60mV because gK is never 0
  • Overall current of Na dependent on # of channels, probability of channels being open, and the current of Na per channel
  • The factor that is most variable is the probability of the Na channels being open, which depends on the Vm (high probability when Vm is >-50mV, low probability if <-55mV)
26
Q

Firing an AP 3

A
  • A few ms after opening the Na channels spontaneously inactivate and prevent further influx of Na
  • Inactivation must occur before the Na channel can be opened again
  • When the Na channels inactivate, voltage-gated K channels (sensitive to depolarization) begin to open and release K from the cell
  • This increases gK and thus (in combination w/ the inactivated Na channels) hyperpolarizes the cell
  • K channels remain open for longer, contributing the the overshoot as the cell hyperpolarizes past resting potential until gK returns to resting state
27
Q

Threshold

A
  • Threshold occurs at the point where the resting net outward current carried by K becomes a net inward current carried by Na
  • This requires a lot of open Na channels per square um
  • For weak stimuli, K efflux still exceeds Na influx and no AP is produced
  • For a strong stimuli, Na influx will exceed K efflux, threshold will be reached, and AP will be produced
  • For AP propagation there must also be enough Na channels in the membrane at the adjacent areas to allow the Na influx to exceed the K efflux (net current flow to be inward)
  • Amplitude of AP is constant throughout the axon and will not be larger due to a stronger stimuli
28
Q

Propagation of APs

A
  • The depolarization of an axon occurs in segments when the axon is myelinated
  • This is because the myelin sheath (extensive wrappings of oligodendrocyte membrane in CNS) covers the axon in parts, and in these places there are few Na channels
  • The sheath is discontinuous, and the places where there is no sheath (node of ranvier) is where the Na channels are located (in high numbers)
  • Therefore the APs jump from one node to the next (saltatory conduction) as each node becomes depolarized by the activation of the previous one
29
Q

Function of myelin

A
  • The myelin sheath prevents Na ions from leaving the axon cytoplasm into the ECF
  • This is because it increases the resistance of passing through the member for the ions
  • This high resistance leads to very little ions escaping out of the cell, retaining the ions in the cytoplasm and increasing the ionic current
  • Overall, this leads to an increase in the conduction velocity of the axon
  • Unmyelinated axons lose more Na ions into the ECF and therefore have a lower conduction velocity than myelinated axons
  • Large diameter axons have higher conduction velocities than small diameter axons
30
Q

Graded response

A
  • Responses to stimuli that are too small to generate an AP
  • Instead they create membrane potential changes (local responses) that decrease exponentially with increasing distance from the site of stimulation
  • The rate of decrease in membrane potential is based on lambda (length constant), which represents how much current is lost thru the membrane (thus myelin increases lambda)
  • The depolarization of a stretch of cell membrane by this mechanism is electrotonic conduction
  • In this the ionic influx from the initial stimulus alone is causing the depolarization, and voltage-gated channels do not contribute
31
Q

Synaptic plasticity

A
  • Change in strength of a synapse btwn two cells
  • Underlies the phenomena of classical conditioning where an organism associates an unconditioned pathway (salivation at smell of food) with a conditioned pathway (ringing a bell every time they are fed)
  • This generates the association of food and the bell and leads to salivation at the sound of the bell
32
Q

Long-term potentiation (LTP)

A
  • High frequency stimulation (100 Hz for 900 pulses) results in enhanced synaptic strength of the postsynaptic cell
  • LTP has 2 properties: input specificity and associativity
  • Input specificity: only the input that has undergone high-frequency stimulation expresses LTP
  • Associativity: a weak input cannot be potentiated by itself. If it is coupled w/ a strong input it can be potentiated together w/ the strong input
33
Q

LTP induction mechanisms 1

A
  • Strong synaptic stimulation (100 Hz, a strong input) can stimulate LTP on its own
  • A weak stimulation (10 Hz, a weak input) will induce LTD (long term depression) instead, unless it is spatially near a strong input from another neuron
  • Ca influx is important for signaling biochemical changes that lead to enhanced synaptic responses
  • Blocking [Ca] rises by adding chelators or channel antagonists prevents induction of LTP
  • Duration and amplitude of [Ca] rise in the cell determines whether LTP or LTD is produced
34
Q

LTP induction mechanisms 2

A
  • NMDA receptors are required for LTP (blocking them prevents LTP generation
  • These receptors have 2 requirements that must be met to be functional: glutamate binding and cell depolarization
  • An excitatory synapse usually contains NMDA and AMPA receptors (both bind glutamate)
  • The glutamate must bind to NMDA to allow for proper conformational change, and bind to AMPA to induce EPSP (depolarization)
  • The depolarization kicks out the Mg that remains in the NMDA channel, fully activating the channel which allows both Ca and Na to enter the cell (confers associativity of LTP)
  • The AMPA channel activation and depolarization is the strong input necessary to induce NMDA activation and thus LTP
35
Q

LTP expression mechanisms

A
  • In principle both pre and postsynaptic changes can lead to LTP, but mostly postsynaptic changes are observed
  • Presynaptic changes: increase in quantity of NTs releases
  • Postsynaptic changes: increase in number and function of AMPA receptors
  • Phosphorylating AMPA receptors leads to an increase in receptor conductance, thus LTP/LTD can be controlled by phosphorylation of AMPA receptors
36
Q

Mechanisms for induction of AMPA receptors

A
  • Brief and large Ca influx from NMDA receptors leads to activation of protein kinases (one is CAMK2)
  • CAMK2 phosphorylates AMPA receptors and increases their conductance for Na
  • CAMK2 also phosphorylates other proteins and leads to an increase in the number of AMPA receptors expressed on the synaptic membrane
  • Overall these two factors leads to easier induction of LTP
  • Prolonged and moderate Ca influx leads to activation of protein phosphatases, which leads to reduced AMPA receptor conductance and expression
37
Q

Silent synapses

A
  • Silent synapses are synapses btwn two cells that do not communicate effectively with each other
  • This is because the post synaptic cell region expresses NMDA only, and thus cannot fully be depolarized
  • These synapses must be converted into functional synapses by other neurons causing depolarization at other locations on the postsynaptic cell
  • This depolarization allows for the activation of the NMDA receptors on the post synaptic membrane
  • In turn this converts the first neuronal synapse into a functional synapse, since the activation of the NMDA channels allows for Ca influx and up regulation of AMPA receptors
  • This process is called synapse maturation, and s crucial for normal brain development
38
Q

Metaplasticity

A
  • The change in synaptic plasticity
  • LTP neuronal connections would generate a positive feedback loop (leading to saturation of the postsynaptic cell) if there weren’t limitations on LTP
  • Thus the more LTP a synapse has the harder it is for that synapse to increase its LTP
  • Likewise, the LTP’d synapse will more easily become LTD if the strong inputs cease (future LTD easier)
  • The same is true for LTD: LTD’d synapses will be more difficult to become more depressed (future LTD harder), and less difficult to become potentiated (future LTP easier)
39
Q

Firing rate homeostasis

A
  • Chronically reducing a cell’s firing rate increases its ability to fire spikes (slow firing neurons want to fire faster)
  • Chronically increase a cell’s firing rate reduces it’s ability to fire (fast firing neurons burn out)
  • These regulations are achieved through modifying synaptic drive to bring firing rate back into a targeted functional range
40
Q

Synaptic scaling

A
  • Chronically changing the cell’s firing rate (at least 2 days) scales the strength of the synapses on the postsynaptic cell multiplicatively (after plasticity occurs)
  • The relative strength of each synapse is maintained (thus retains the memory of what neuron is activating it- the memory trace), but the overall firing rate is kept the same
  • The response to each input (synaptic drive) is modified to maintain firing rate homeostasis, and to preserve the relative strength of each synapse

Neuro (62 decks)

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