Essential neuroscience (A) Flashcards
Why do animals have nervous systems
Sense and respond to their environment Homeostatic regulation of internal functions (homeostasis = maintenance of a relatively stable internal environment). 2 major regulatory systems:
endocrine v nervous system - system tyoe
endocrine - wired, nervous - wireless
endocrine v nervous system - - target
endocrine - specificity of target cell binding, nervous - anatomical connection with target cells
endocrine v nervous system - distance
endocrine - hormones carried in the blood over a long distance. nervous - neurotransmitters diffuse through a short distance
endocrine v nervous system - response time
endocrine - slow and long-lasting. nervous - rapid and brief response
endocrine v nervous system - what does it coordinate
endocrine - long lasting activities (growth, etc) nervous - coordinates fast and precise responses
endocrine v nervous system - voluntary or involuntary
endocrine - involuntary. nervous - voluntary/involuntary
endocrine v nervous system - influence
endocrine - influences CNS output. nervous system - influences endocrine output
What is gyrification
folding of the cortex - allows a larger cortical surface area and hence greater cognitive functionality to fit inside a smaller cranium. Enhances efficient neural processing
What are the 2 divisions of neural tissue
grey matter and white matter
what is grey mattter
neuronal cell bodies
what is white matter
myelinated neurites projecting from neurones
What division is the CNS
Sensory/afferent division – brings sensory information to the CNS from receptors in peripheral tissues and organs
What makes up the preipheral nervous system
Cranial nerves: 12 pairs
Spinal nerves: 31 pairs
What division is the peripheral nervous system under
Motor/efferent division – sends motor commands from the CNS to target organs (muscles, glands)
What are the 2 parts of the peripheral nervous system
SOMATIC AND AUTONOMIC
What is the somatic nervous system
motor neurons to skeletal muscle. Voluntary control.
What is the autonomic nervous system
neurons to visceral organs (e.g., heart). No voluntary control. Sympathetic and parasympathetic.
How is a neuron’s function anatomically compartmentalised
input, intergrative, conductive, output
What is the cell body
contains nucleus, golgi and most organelles
what are neurites
long, filamentous extensions responsible for propagating action potentials
What are synpases
responsible for transmitting information between neurons via neurotransmitter signalling
What do synapses allow for
information to pass between neurons
what does the pre-synapse release
neurotransmitters
What does the post-synapse carry
carries neurotransmitters sensitive ion channel receptors that can have excitatory or inhibitory effect on the target neuron.
sensory neuron function
detection of external and internal information: light, vibration, temperature, pressure and stretch
motor neuron function
Outputting information from the central nervous system to muscles, driving behavioral response
interneuron function
connecting neurons to each other, amplifying and attenuating activity of a neuronal circuit by integrating additional data
Which cells support neurons
glial cells
what are astrocytes
‘Star-shaped’ glia, supporting neuron function and delivery of molecules to/from the vasculature
when are astrocytes activated
Activate in response to injury, neuroinflammation or degeneration in the brain
non-reactive astrocytes
trophic support of neurons, synapase formation and maintenance, clearance of neurotransmitters
reactive (inflamed) astrocytes
damage neurons, activate microglia, some phagocytic activity
what are microglia
Resident immune cell of the brain, surveying for pathogens and damaged material. Important roles in development and pruning of excess synpases
When do microglia become inflamed
in response to pathogens (virus, bacteria, etc) injury and neurodegeneration
morphological and functional changes of microglia when activated
increased motility, phagocytosis and release of immune factors (cytokines)
how do myelinating glia myelinate neurons
by insulating them in multiple layers of sphingolipids, increasing axon potential speed
what do oligodendrocytes do
myelinate multiple axons
what do schwann cells do
myelinate single axons
which axons are myselinated
All motor axons are myelinated, and some sensory axons
Different cell culture models to measure the function of the nervous system
- Stable cell lines – easy to grow, derived from tumors
- Primary neuronal cultures (derived from model organisms)
- Human stem cell derived cultures (derived from skin cells of living patients)
- Advances in cell culture technique now allow researchers to grow 3D ‘mini brains’
- Powerful tools for pharmacological testing, genetic screening and electrophysiology
common model organisms in neuroscience research
- Rodents (mouse, rat)
- Zebrafish (Dario renio)
- Zebra finch (Taeniopygia guttata)
- Fruitfly (drosophilia melanogaster)
- Nematode worms (caenorhabditis elegans)
- Ethical considerations – must have justification for use of vertebrates, strict regulation of experiments
how can behavioural responses be manipulated
pharmacologically and genetically
what can excitable cells do
Excitable cells can propagate an action potential across their membrane and include: muscle (myocytes, cardiomyocytes), endocrine cells, neuronal cells
what are the important properties of a membrane
- composed of hydrophobic lipids, impermeable to water soluble molecules
- Channels/pumps facilitate cross membrane transport of ions and molecules
- Channels/pumps are selective, based on size, charge and solubility of substrates
How do ions move down an electrical gradient
positive to negative charge
electrophysiological activity
Important, widely used technique for measuring neuron activity in cell culture and model organisms
what does and intracellular microelectrode and an extracellular electrode measure
intra - measures internal voltage. extra - extracellular voltage
how can we record the membrane potential of the cell of interest
The difference in voltage recorded between intra- and extracellular electrodes
What is resting potential
the point at which difference in ion concentrations are stable across a membrane
Under resting potential neuronal membranes are:
- Permeable to passive diffusion by K+, Na+ and Cl-. Ions pass through ‘leaky’ channels (not through the lipid bilayer)
- Impermeable to intracellular large anions, organic acids, sulphates, phosphates, amino acids. Too large to pass through the membrane channels
how are ion concentration gradients maintained
by active transporters
how do active transporters utilize energy
Active transporters utilize energy from ATP hydrolysis, pump ions against the chemical gradient. Na+ - K+ pump exchanges 3 intracellular Na+ ions for 2 extracellular K+ ions
where is there high K+
in the neuronal cytoplasm
where is there high Na+
in the cytosol
how is neuronal K+ buffered
by membrane impermeable organic anions (negative charge), but membranes are permeable to K+
how is a steady chemical and electrical gradient established
combined passive diffusion and active transport
what prevents K+ diffusion at resting potential
negative intracellular electrostatic forces
at rest what is yhe K+ equilibrium potential
-90mV
Sodium ions at resting potential
positive charge with low permeability across the neuronal membrane (Ena = +55mV)
Sodium ions at resting potential
positive charge with low permeability across the neuronal membrane (Ena = +55mV)
Sodium ions at resting potential
positive charge with low permeability across the neuronal membrane (Ena = +55mV)
Chloride ions at resting potential
negative charge, passively distributed and dependent of Na+ and K+ distribution (ECl = -60mV)
What is the resting potential of the neuronal membrane
-70 mV
What triggers an action potential
by input stimulation of inward current, caused by activation of post-synaptic receptors on the neuronal membrane. inwards flow of positive ions
what triggers neurotransmitter release
stimulated by action potentials reaching the pre-synaptic terminal
what triggers neurotransmitter release
stimulated by action potentials reaching the pre-synaptic terminal
Why can information travel long distances
Cascading reversal of membrane potential transmits a signal across neurite membranes to the synapse
What are the 4 phases of an action potential
depolarisation , repolarisation, hyperpolarisation, afterpolarisation
what happens during depolarisation 1
rapid positive change in membrane potential from –70mV to ~+30mV
What happens during repolarisation
rapid negative change in potential
How long does the depolarisation - repolarisation spike last
~1ms
What happens during hyperpolarisation
membrane potential becomes more negative than resting potential
What happens during afterpolarisation
membrane potential returns to resting potential state
What is a threshold stimuli
stimulation needed to achieve an action potential. every cell has a different threshold. ~15mV below resting potential
what is the absolute refractory period
During the spike, a neuron cannot be stimulated
hat is the relative refractory period
During hyperpolarisation and afterpolarisation, a suprathreshold stimulus (I,e,. Larger) is required to trigger an action potential
hat do refractory periods allow for
unidirectionality (blocks them from travelling in the reverse dircetion) of action potentials and an upper limit on firing rate
How are action potentials unidircetional
Action potentials create an active zone region of local difference in membrane potential. Differences in membrane induce a local circuit. Current spreads from the negative active zone to positively charged surrounding membrane
How does ion flow occur
through specialised transmembrane voltage dependent ion channels
what are the key properties of voltage dependent ion channels
- Ion specific – generally only one specific ion can pass through a channel
- Voltage sensitive – channels open/close in response to changes in membrane potential
Where on the axon are action potentials triggered
axon hillock - has the lowest threshold across the cell
What does the stimulus threshold being released cause
Na+ channels opening triggering an action potential
Ion movement - depolarisation
voltage gated Na+ channels open rapidly – Na+ enters the cell, voltage gated K+ channels slowly open
ion movement - repolarisation
Na+ channels close slowly. Voltage gated K+ channels continue to open – K+ leaves the cell
Ion movement - hyperpolarisation
K+ continues to enter the cell, K+ channels close slowly
Ion movement - afterpolarisation
K+ and Na+ actively transported, membrane returns to resting potential
What are the 2 forms of synapses
- Electrical synapses – transmission by current
- Chemical synpases – transmission by chemical
Features of electrical transmission
instantaneous, bidirectional transmission of signal via ion current . Allow for electrical coupling of adjacent cells. Rapid repsonse. Highly synchronised neuronal firing
Electrical synapse - gap junction
Gap junction connections composted of hemichannels on pre and post synaptic side of membrane, each formed by six connexin proteins
Gap junctions close in response to elevated Ca2+
Also have important roles in glia (astrocyte Ca2+ signalling. Schwaan cell layers)
Chemical synaptic junctions
Signal transduction is not facilitated through direct cell contact. A chemical signal is transmitted across a cleft, or gap between cells. Diffusion of a chemical signal across the cleft is slower than electrical transmission across gap junctions. Chemical transmission allows for amplification of signal to the target neuron
What defines a neurotransmitter
- Synthesized in the presynaptic neuron
- Can be released into the synaptic cleft and elicit a response in target neurons when present in sufficient concentration
- Can be experimental added to a target neuron and cause same response as endogenous transmitter release
What type of signal is given by the chemical synaptic junction
excitory or inhibitory - depends on type of receptor
Where are axodendritic synpases usually found
synapses are most common in the brain, with pre-synapses trageting post-synpatic receptors in dendrites
In ‘spiny’ neurons, axo- dendritic post-synapses form on specialised spine structures
Where can post-synaptic receptors be found
in other compartments of the target neuron
What is axosomatic
synapsing at the cell body
What is axoaxonic
synapsing at the axon (or presynapse)
What do pre-synaptic terminals contain
synaptic vesicles (specialised vesicles loaded with neurotrnsmitters)
Where do synpatic vesicles release their content
dock with the synaptic membrane, releasing their conetent across the synaptic cleft (~20nm)
what are chemical synapses enriched for
energetically demanding, and enriched for energy producing mitochondria
How can post-synapses be identified
by a post-synaptic density, a region enriched from receptors and associated machinery
Function of glia found at the synaptic junction
support synpase function, particularly clearance of transmitters from the cleft
What stimulates neurotransmitter release
action potentials recahing the pre-synaptic bouton and triggering a Ca2+ influx through voltage-dependent calcium channels
What does increased calcium in the terminal activate
fusing of synaptic vesicles with the presynaptic terminal
What do the released neurotransmitters do when they have crossed the synaptic cleft
, bind their type specific receptors and trigger ion influx to either stimulate or supress an action potential in the target neuron
Synaptic vesicle neurotransmitter release - neurotransmitter uptake (1)
neurotransmitters are loaded into synaptic vesicales by active transporters. Active transporters are selective for specific neurotransmitters
Synaptic vesicle neurotransmitter release - reserve pool (2)
synaptic vesicles loaded with neurotransmitters are intially tethered to the actin cytoskeleton by snapsin 1. Reserve pool synaptic vesicles can be released from the cytoskelton by Ca2+ dependent phosphorylation of synapsin 1
Synaptic vesicle neurotransmitter release - docking (3)
synaptic vesicles are recruited from the reserve pool to a reasable pool at the pre-synaptic membrane. Reserve pool vesicles are released from the cytoskeleton by calcium depndent phosphorylation of synapsin 1 (by kinases including PKC). Releasable pool synaptic vesicles are located at the active zone
Synaptic vesicle neurotransmitter release - priming (4)
ATP dependent process partially fusing synaptic vesicles with the pre-synaptic membrane. Priming and subsequent fusion are facilitated by ‘SNARE’ proteins. V – snare: located on the synaptic vesicle synaptobrevin. T-snare: located on the presynaptic terminal syntaxin, SNAP-25. Without Ca2+ bound, synaptotagmin blocks fusion
Synaptic vesicle neurotransmitter release - calcium influx (5)
action potentials trigger a rapid influx of Ca2+ through voltage dependent channels. Activates calcium dependent proteins. Fusion: calcium binding to synaptotagmin causes a confirmational changes, allowing SNARE facilitated membrane fusion to occur. Synaptic vesicle neurotransmitter contents are released into the cleft
Synaptic vesicle neurotransmitter release - step 6
Synaptic vesicles are coated with endocytic proteins clathrin. Mmembrane bending recovers the synaptic vesicle membrane. Dynamin facilitates scission of the vesicle from in the membrane (activated through GTP -> GDP + P hydrolysis. Clathrin is removed from the vesicles.
Synaptic vesicle neurotransmitter release - step 7
Recovered synaptic vesicles are acidified by active pumping of H+ for neurotransmitters via specific vesicular transporters:
1. VGLUT: vesicular glutamate transporter
2. VMAT: vesicular monoamine transporter (serotonin, dopamine, adrenaline, noradrenaline, histamine)
3. VAchT: vesicular acetylcholine transporter
4. VGAT: vesicular GABA transporter
what can block neurotransmitter relase
toxin target SNARE proteins
What is botulinum neurotoxins
peptide toxins composed of a heavy and light chain. Derived from Clostridium botulinum
How can botulinum prevent neurotransmitter release
- BoNTs bind synaptic terminals of aetyl-choline releasing neurons and internalised by endocytosis
- Once within the cytoplasm, light chains of BoNTs A and E bind and cleave the c-terminal of t-SNARE SNAP25 via metalloprotease activity
- Disruption of SNAP 25 results in failure of neurotransmitter vesicles to fuse at the synaptic terminal
What applications does botulinum neurotoxins have
theraputic application beyond cosmetics, treatment of epileptic seizures and muscle spasms
What is tetanus toxin (tetanospasmin)
peptide toxins derived from Clostridium tetani
What does teatnus toxin bind to
s pre-synaptic membrane glycoprotein/lipids in neuromuscular junction and enters motor neuron through endocytosis
Where is tetanus toxin transported to
the central nervous system and released into synaptic clefts, where it is internalised by inhibitory interneurons. Tetanus toxins access the presynaptic membrane, then binds and cleaves synaptobrevins VAMP 1 / 2
Tetanus toxin causes a loss of regulatory GABA release, what does this result in
overactivity of motor neuron and powerful, dmaaging muscle spasms
How are neurotransmitters produced
through enxymatic metabolism of precursors
Where are small amino acid neurotransmitters synthesised
enzymatic processing occurs in the cytosol (cell body or pre synaptic terminal). Transmitters are packaged into synaptic vesicles
Where are large neuropeptide neurotransmitters synthesised
Produced as pre-peptides in the soma ER-Golgi. Packaged into dense-core vesicles. Transported to presynaptic terminal for processing and secretion
What is the most common excitatory neurotransmitters
glutamate - CNS. pyramidal neurons - cortex. granule cells - cerebellum
How is glutamate synthesised
Metabolised by cytosolic Glutaminase enzyme from precursor Glutamine
How is glutamate loaded into synaptic vesicles
VGLUT transporter
How is glutamate cleared from the synaptic cleft
by neuronal and astrglial glutamate transporters
What do neurons do to glutamate
return to metabolic pool or reloaded into synaptic vesicles
What do astrocytes do to glutamate
Glutamate converted to glutamine by glutamine synthetase. Secreted from astrocytes and taken up by neuronal glutamine transporters
What is the most common inhibitory neurotransmitter in mammalian CNS
GABA
How is GABA synthesised
from glutamate by glutamic acid decarboxylase (GAD)
What produces GABA
lpha-ketoglutarate, a produce of the mitochondria Krebs cycle
What loads GABA into synaptic vesicles
VGAT - vesicular GABA transporter
What clears GABA from the synaptic cleft
be neuronal and astroglial GABA transporters
GABA and neurons
GABA return to metabolic pool or reloaded into synaptic vesicles
GABA and astrocytes
GABA converted to glutamine and enters the glycine processing pathway to return to neurons
Fast transmission
ligand gated ion channels induce changes in post-synaptic membrane potential in milliseconds
Slow transmission
Metabotropic receptors coupled to secondary messengers. Slowe (milliseconds-minutes) and long lasting (minutes-days) changes
What do ionotrophic receptors allow for in EPSPs
influx of Na+, K+ and Ca+ membrane depolarisation
How many excitatory post-synaptic potentials are needed to stimulate an action potential
Many EPSPs stimulating a post-synaptic membrane within ~10ms are required to overcome threshold and induce an action potential
What are IPSPs
inhibitory post synaptic potentials
What do iontrophic receptors allow for in IPSPs
allow influx of Cl-. Reduced change of membrane reaching threshold.
What ligan-gated ion channels are included in the cys-loop family
Ionotrophic channels including those for acetylcholine, GABA, Glycine and serotonin
What are all cys loop receptors
pentamers of subunits forming a pore
What defines channel activity
Combinations of alpha, beta, gamma and delta subunits defines channel activity (physiological function, pharmacology)
How can we see what channels actually look like
Advanced ‘cryo’ electron microscopy
How are glutamate receptors defined
by selective inhibitors - are all tetrameric
What are the 3 categories of glutamate receptors
- AMPA - GluR1, GluR2 (voltage gating, Ca2+ slectivity), GluR3, GluR4
- Kainate – GluR5, GluR6, GluR7. Functions less well described, more limited distribution
- NMDA – heterotetramer of NR1 (8 isoform), NR2 (4 isoforms) NR3 confers inhibitory activity. Voltage gated – depolarisation requires to activate. Allow large Ca2+ permeable, allowing activation of secondary messengers. Roles in long term potentiation and long term depression
What blocks the NMDA receptors at resting potential
voltage gated Mg2+ ions, removed by membrane depolarisation
How can NMDA receptor activity be potentiated
by binding of co-agonists, D-serine and glycine
Why can NMDA receptors allow for longer term activation of secondary messengers
because they are permeable to Ca2+
What does modulation of AMPA receptor activity allow for a role in
long-term potentiation and long-term depression
what activates metabotropic receptors
neurotransmitters
Why do metabotropic receptors have slow transmission
indirect activation of ion channels
What does activation of metabotropic receptors lead to
a down stream signalling cascade
What effect on neuronal activity do metabotropic receptors have
excitatory or inhibitory
Metabotropic receptors long-term effects
neuronal function and morphology
What is homosynaptic depression
reduced activity within the pathway - I.e., not requiring a modifying cell
Short-term habituation
Aplysia exposed to 10 stimuli = habituated response lasts several minutes
Long-term habituation
Aplysia exposed to 10x stimuli x 4 sessions = habituated response lasts several weeks
What is sensitisation
learning to avoid a noxious stimulus
What is facilitisation
increased strength of post-synaptic potential to a stimulus if closely paired with a prior stimulus
What is dishabituation
overcoming a habituated response
What is heterosynaptic processing
synapse activity altered by a modifying neuron
What do modulatory inter-neurons release in the short-term sensitization signaling cascade
serotonin (5-HT) onto G-coupled 5-HT receptors on presynaptic terminals of sensory neurons
short-term sensitization signaling cascade - pathway 1
- Secondary messenger cyclic adenosine monophosphate produced in presynapse
- Activation of cAMP dependent protein kinase A (PKA) [NB PKA has 2 catalytic and 2 regulatory subunits]
- Phosphorylation induced closing of outwards K+ channel extend action potential, increasing presynaptic Ca2+ levels
- Increased calcium promotes increased neurotransmitter release
short-term sensitization signaling cascade - pathway 2
- Enhanced activation of phospholipase C (PLC)
- Increased production of diacylglycerol (DAG) activates protein kinase C (PKC)
- Phosphorylation of presynaptic proteins increases mobilisation of reserve glutamate vesicles to releasable vescile pool
What does short-term sensitization do
increase synaptic release for minutes - hours
Consolidation
Long-term sensitization requires more stable changes in synaptic function and architecture
Long-term sensitization - what causes altered gene expression
Sustained activation 5-HT metabotropic receptors
Long-term sensitization - result of activation of CREB regulated genes
results in increased production of synpases, changing the morphology of neurons and strengthening its activity
