MInimod 3 - Essential Neuroscience A Flashcards
(143 cards)
1
Q
Why do animals have a nervous system?
A
Sense and respond to their environment
2
Q
What is the sensory/ afferent division?
A
- brings sensory information to the CNS from receptors in peripheral tissues and organs
3
Q
What 2 sections make up the PNS?
A
Motor / Efferent division
* motor neurons to skeletal muscle
* Voluntary control
Autonomic nervous system
* neurons to visceral organs (eg heart)
* No voluntary control
* Sympathetic
* Parasympathetic
4
Q
What is homeostasis?
A
Maintenance of a relatively stable internal environment
5
Q
What are the 2 major regulatory systems for homeostasis?
A
Endocrine system
Nervous system
6
Q
Describe the features of the endocrine system.
A
- wireless system
- specificity of target cell binding
- hormones carried in the blood to long distance
- slow and long-lasting response (sec to hours)
- controls long lasted activities (growth, reproduction, metabolisms)
- involuntary
- influences CNS output
7
Q
What are the features of the nervous system?
A
- wired system
- anatomical connection with target cells
- neurotransmitters diffuse through short distances
- rapid and brief response (msec-sec)
- coordinates fast and precise responses
- voluntary / involuntary
- influences endocrine output
- has other non-regulatory functions
8
Q
What is the central nervous system?
A
- brain, brainstem and spinal cord
9
Q
What is the gyrification of the cortex? What does this result in?
A
The human cortex has undergone gyrification, folding of the cortex. This process is seen in all primates, but not all mammals which often have a smooth cortex surface.
All regions of the CNS constrain 2 divisions of neural tissue - grey and white matter
10
Q
What is grey matter made of?
A
Primarily neuronal cell bodies
11
Q
What is white matter made of?
A
Myelinated neuritis projecting from neurons
12
Q
What are the 6 regions of a model neuron?
A
- input
- integrative
- conductive
- output
13
Q
What are the 5 different types of neurons? What does they all lead to at their output ends?
A
Sensory neuron - central neuron
Motor neuron - muscle
Local inter neuron - central neuron
Projection inter neuron - central neuron
Neuroendocrine cell - capillary
14
Q
What are the 3 main compartments of a neuron? What does they do?
A
- Neurites - long, filamentous extensions responsible for propagating action potentials
- Synapses - repsonsible for transmitting information between neurons via neurotransmitter signalling
*cell body - containing nucleus, Golgi and most organelles
15
Q
What are synapses? What do they allow?
A
Synapses are a unidirectional chemical junction between neurons
Synapses allow neurons to transmit signals to other cells
16
Q
What are the functions of pre and post synapses?
A
- presynapse releases neurotransmitters
- Post synapse carries neurotransmitter sensitive ions channel receptors that can have excitatory or inhibitory effect on the target neuron
17
Q
How are neurons specialised?
A
Neurons rarely act in isolations, instead forming a complex, interconnected networks of neuron subtypes with highly specialised functions-
Eg sensory, motor, inter neuron
18
Q
What are sensory neurons?
A
detection of external and internal information: light, vibration, temperature, pressure stretch
19
Q
What is an inter neuron?
A
outputting information from the central nervous system to muscles, diving behavioural response
20
Q
What are neurons supported by?
A
Neurons are also supported by essential, specialised glial cells throughout development and ageing
‘Glia’- glue: these cells we historically thought to just hold the brain together
Astrocytes
21
Q
What are Astrocytes? What are the 2 types?
A
Astrocytes
* star shaped glia, supporting neuron function and delivery of molecules to/from the vasculature
* Activate in response to injury, neuroinflammation or degeneration in the brain
Non-reactive - trophic support of neurons, synapse formation and maintenance, clearance of neurotransmitters
Reactive - (inflamed) - damaged neurons, activate microglia, some phagocytes activity
22
Q
What are motor neurons?
A
outputting information from the central nervous system to muscles, diving behavioural response
23
Q
What are interneurons?
A
Intermeuron - connecting neurons to each other, amplifying and attenuating activity of a neuronal circuit by integrating additional data
24
Q
What are neurons supported by?
A
Neurons are also supported by essential, specialised glial cells throughout development and ageing
‘Glia’- glue: these cells we historically thought to just hold the brain together
Astrocytes
25
What are astrocytes and what are the 2 different types?
Astrocytes
* star shaped glia, supporting neuron function and delivery of molecules to/from the vasculature
* Activate in response to injury, neuroinflammation or degeneration in the brain
Non-reactive - trophic support of neurons, synapse formation and maintenance, clearance of neurotransmitters
Reactive - (inflamed) - damaged neurons, activate microglia, some phagocytes activity
26
What are microglia? When do they become inflamed?
Resident immune cells of the brain, surveying for pathogens and damaged material
Important roles in development and pruning of excess synapses
Become inflamed in response to pathogens (virus, bacteria etc) injury and neurone generation
27
How do microglia change when activated?
Morphological and functional changes when activated : increased motility, phagocytosis and release of immune factors (cytokines)
28
What are myelinating glia? What are they made out of?
Myelinated neuron by insulating them in multiple layers of sphingolipids, increasing axon potential speed
CNS and PNS have different glia performing the same role
29
What are the 2 different myelinating glia in the CNS and PNS?
CNS and PNS have different glia performing the same role
Oligodendrocytes: myelinated multiple axons
Schwann cells : myelinated single axons, all motor axons are myelinated and some sensory axons
30
How do researchers measure function of the nervous system?
in vitro cells
Stable cell lines - easy to grow, derived from tumours
Primary neuronal cultures (dervided from model organisms)
Human stem cell derived cultures (derived from skin cells of living patients)
Advances in cell culture technique now allow researcher to grow 3D ‘mini brains’
Powerful tools for pharmacological testing, genetic screening and electrophysiology
31
What are common model organisms in testing?
Model organisms are a powerful way to understand how nervous system functions
Common module organisms include - rodents, zebrafish, zebra finch, fruit lay, nematode worms
32
How can behavior range? What can it be influenced by? Where are behavioral deficits seen?
Behavior range form simple reflexes to complex learning and memory
Behavioral responses can be manipulated pharmacologically, genetically
Behavioural deficits are seen in models of developmental disorders and neurodegenerative diseases
33
What are membrane potentials? Examples of excitable cells?
Most cells have a small difference in membrane potential however not all cells are excitable
Excitable cells can propagate an action potential across their membrane include:
Muscle (myocytes, cardiomyocytes)
Endocrine cells
Neuronal cells
34
What are the 3 main membrane properties?
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 soluability of substrates
35
What is a concentration gradient?
Molecules move down concentration gradients ie high concentration to low concentration
36
What is intracellular recording? How do we get the membrane potential?
Intracellular microelectrode: measure internal voltage
Extracellular electrodes: measures extracellular voltage
The difference in voltage recorded between intracellular and extracellular electrodes gives us the membrane potential of the cells of interest
37
What is an electrical gradient?
Ions moves down concentration gradients ie positive charge to negative charge
38
What is electrophysiological activity?
Important, widely used technique for measuring neuron activity in cell culture and model organisms
39
What is resting potential?
- when unstimulated, excitable membranes are held at resting potential
- resting potential is the point at which difference in ion concentrations are stable across a membrane
40
Describe neuronal membranes under resting potential?
- permeable to passive diffusion by k+, Na+ and Cl- (ions pass through leaky channels, not through lipid bilayers)
- impermeable to intracellular large anions (organic acids, sulphates, phosphates, amino acids, too large to pass through the membrane channels)
41
How are Na+, K+ and other ion concentration gradients maintained?
Maintained by active transporters
- active transporters utilise energy from ATP hydrolysis, pump ions against chemical gradient
42
What does the Na+-K+ pump exchange?
3 intracellular Na+ ions for 2 extracellular K+ ions
- uses 1 atp - ADP
43
How is resting potential established?
Resting potential is an established chemical/ electrical equilibrium.
- neuronal cytoplasm is high in potassium (K+), the extracellular fluid is high in sodium (Na)
- neuronal K+ is buffered by membrane impermeable organic ions (negative charge)
- cell membranes are permeable to K+, allowing diffusion to occur
- negative intracellular electrostatic force prevents further K+ diffusion
44
How does potassium contribute to an equilibrium potential? What other factors also contribute?
- combined passive diffusion and active transporters utilise energy reach a steady chemical and electrical gradient
- potassium reaches an equilibrium potential (EK) of -90mV (measured as the difference between inside and outside of the cell)
- resting potential is primarily the result of potassium gradient across the neuronal membrane, although other factors also contribute
Sodium ions - positive charge with low permeability across the neuronal membrane (ENa = +55mV)
Chloride ions - negative charge, passively distributed and dependent of Na+ and K+ distribution (Ecl = -60mV
SO NEGATIVE NUMBER MEANS HIGHER IN CELL AND POSTIVE NUMBER MEANS HIGHER OUT OF THE CELL
45
What is the resting potential of a neuronal membrane?
Combining all equilibrium potentials of the ions you get a neuronal membrane that has a resting potential of -70mV
46
What are action potentials? What are they triggered by?
Action potentials allow neurons to transmit information along their membrane
Action potential are. A short lived reversals of membrane potential
Action potentials are triggered by input stimulation of inward current, caused by activation of post synaptic receptors on the neuronal membrane
47
How does an action potentials travel? End result?
Cascading reversal of membrane potential transmits a signal across neurite membranes to the synapse, allowing information to rapidly travel long distances
Nuerotranmitter release is stimulated by action potentials reaching the pre-synaptic terminal
48
What are the 4 phases of action potential activity?
Depolarisation
Repolarisation
Hyper polarisation
After polarisation
49
What are action potentials triggered by?
Action potentials are triggered by an input of inward current caused by an inward flow of positive ions
50
What is stage 1, depolarisation of the membrane?
Depolarisation - rapid positive change in membrane potential from -70mV + 30mV
51
What is stage 2, repolarisation?
Repolarisation - rapid negative change in potential
52
How long does the depolarisation-repolarisation spike last for?
Depolarisation- repolarisation spike lasts -1ms
53
What is stage 3, hyperpolarisation?
Hyperpolarisation: membrane potential becomes more negative than resting potential
54
What is stage 4, after polarisation?
After polarisation: membrane potential returns to resting potential state
55
When will an action potentials be propagated?
- not all stimulation is sufficient to induce an action potential
- a threshold stimulus of input must be achieved to trigger a potential on 50% of the occasions
- all neurons have diffferent threshold stimuli, usually around -15mV positive of resting potential (ie -55mv from -70mV)
56
What is meant by an action potential being ‘all or nothing’?
- insufficient stimuli will not trigger an action potential being
- once triggered the action potential of a neuron are all of similar amplitude
57
What does a refractory period ensure?
Refractory period regulates action potential firing
- once an action potential is stimulated, a neuron in the spike period cannot be initiated again
58
What are the 2 types of refractory period?
Absolute refactory period
Relative refractory period
59
What is the absolute refractory period?
During the spike (depolar-repolar) a neuron cannot be stimulated
60
What is a relative refractory period?
During hyperpolarsation and afterpolarisation, a supra threshold stimulus (ie larger) is required to trigger an action potential (because for some time the mV is subsequently MORE negative than resting)
61
What do refractory periods allow for?
- unidirectionality of action potentials
- an upper limit on firing rate
62
What is meant by an active zone and the creation of a local circuit in action potentials?
- 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
- refractory period blocks action potentials from travelling in the reverse direction
63
How are action potentials driven by voltage dependent ion channels?
Action potentials are the result of ion flow across the membrane, between neuron and extracellular fluid
- ion flow occurs through specialised transmembrane voltage dependent ion channels
64
What are the 2 key properties of voltage dependent ion channels?
1 - ion specific (generally only one specific ion can pass through the channel)
2 - voltage sensitive - channels open/ close in response to change in membrane potential
65
Where are action potentials initiated from?
Action potentials initiate in the axon hillock which is a specialised region
- the membrane of the axon hillock has the lowest threshold across the cell
- voltage gated sodium channels (inward) are enriched in within the hillock region
66
Where is input and integrative information encoded?
Input and integrative information is encoded in the dendrites and soma, which anatomically precede the hillock region
67
What ion predominantly triggers an action potential?
Stimulus threshold results in most Na+ channels being open, triggering an action potential
68
Describe ion activity during depolarisation?
- voltage gated Na+ channels open rapidly, Na+ enters the cell
- voltage gated K+ channels slowly open
- rapid increase in mV
69
Describe ion activity during repolarisation?
- Na+ channels close slowly
- voltage gated K+ channels continue to open: K+ leaves the cell
- mV rapidly becomes more negative
70
Describe ion activity during hyperpolarisation?
- K+ continues to enter the cell, K+ channels close slowly
- very negative mV value
71
Describe ion activity during afterpolarisation
- K+ and Na+ actively transported, membrane returns to resting protential
72
What does myelination increase?
Myelination increases the speed of action potential propagation
- nodes of ranvier allow rapid spread of depolarisation
- saltatory conduction (?)
73
What are the 2 different types of synapses found between neurons?
Electrical syspasnes - transmission by current
Chemical synapses - transmission by chemical
74
What are electrical synaptic junctions?
Electrical transmission: instantaneous, bidirectional transmission of signal via ion current
Allows for electrical coupling of adjacent cells
* rapid neuronal response (ie escape reflex)
* Highly synchronised neuronal firing (ie inhibitory inter neurons in mammalian brain)
75
What are electrical synaptic junctions/ gap junctions composed of? How do gap junctions close?
* Gap junction connection composted of hemichannels on pre and post synaptic side of membrane, each formed by six connects in proteins * Gap junction connection composted of hemichannels on pre and post synaptic side of membrane, each formed by six connects in proteins
* Gap junctions close in response to elavated ca2+
76
What are chemical synaptic junctions?
Chemical transmission
Signal transduction is not facilities 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 application of signal to the target neuron
77
What are the 2 types of chemical synaptic junction?
* the neurotransmitters released at chemical synapses can have an excitatory or inhibitory effect of the target cell
* Effect of a neurotransmitter is dependent on the type of receptor (excitatory/inhibitory)
78
What defines a neurotransmitter?
* synthesised in 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
* A process exists to remove the chemical from the synaptic cleft
* The neurotransmitters released at chemical sysnapses can have an exit or or inhibitory effect on the target cell
* Effect of a neurotransmitter is dependent on the type of receptor (excitatory/inhibitory)
79
Where are axodendritic synapses most common? 2 different types?
Synaptic junction are found throughout the target neurons
Axodendritic synpases are most common in the brain, with pre-synapses targeting post synaptic receptors in the dendrites.
In spiny neurons, axo-dendritic post synpases form on specialised spine structures
Spine synapse and shaft synapse
80
What is meant by axosomatic?
Synapsing at the cell body
81
What is meant by axoaxonic?
Synapsing at the axon (or presynapse)
82
What do presynaptic terminals contain?
Pre-synaptic terminals contain synaptic vesicles (-50nm) specialised vesicles loaded with neurotransmitters
83
What is the role of synaptic vesicles?
Synaptic vesicles dock with the synaptic membrane, releasing their content across the synaptic cleft (-20nm0
84
What can be found at chemical synapses to help with its function?
Chemical synapses are energetically demanding, and enriched for energy producing mitochondria
85
Can can post synaptic areas be identified?
Post-synaptic can be identified by a post-synaptic density, a region enriched from receptors and associated machinery
86
What are glia process?
Glia processes, typically astrocytic, are often found at a synaptic junction.
These glia support synaptic function, particularly clearance of transmitters from the cleft
87
What is triggered when action potentials reach pre-synaptic terminal?
Action potentials reaching pre-synaptic terminal trigger an influx of calcium
* neurotransmitter release is stimulated by action potentials reaching the pre-synaptic bouton and triggering a ca2+ influx through voltage dependant calcium channels
88
What triggers synaptic vesicle release?
Elevated calcium in the presynaptic terminal triggers synaptic vesicle release
* increased calcium in the terminal activates fusing of synaptic vesicles with the presynaptic terminal
89
How are post-synaptic receptors activated?
Release neurotransmitters cross the synaptic cleft and activate post-synaptic receptors
* released neurotransmitters cross the synaptic cleft, bind their type specific receptors and trigger ion influx to either stimulate or suppress in action potential in the target neuron
90
What is the vesicle neurotransmitter release cycle?
1. Neurotransmitter uptake
2. Reserve pool
3. Docking
4. Priming
5. Fusion
6. Endocytosis
7. Recycling
8. Formation of early endosome
91
How are neurotransmitters undertaken into synaptic vesicles?
Neurotransmitter uptake: neurotransmitters are loaded into synaptic vesicles by active transporters
Active transporters are selective for specific neurotransmitters
92
Where are neurotransmitter loaded synaptic vesicles stored? Where are they initially tethered and by what? How can they be released from this?
Neurotransmitter loaded synaptic vesicles are stored in a reserve pool
reserve pool: synaptic vesicles loaded with neurotransmitters are initially tethered to the actin cytoskeleton by synpasin 1
Reserve pool synaptic vesicles can be released from the cytoskeleton by ca2+ dependant phosphorylyation of synapsin 1
93
How is neurotransmitter content of synaptic vesicles released? Docking? Where are they located?
Neurotransmitter content of synaptic vesicles are released by calcium dependent exocytosis
Docking - synaptic vesicles are recruited from the reserve pool to a releasable pool at the pre-synaptic membrane
reserve pool vesicles are released from the cytoskeleton by calcium dependent phosphorylation of synpasin 1 (by kinases including PKC)
Releasable pool synaptic vesicles are located at the active zone
94
What is priming? What is this facilitated by?
Priming - ATP dependent process partially fusing synaptic vesicles with the presynaptic terminal Release-synaptic membrane
Priming and subsequent fusion are facilitated by SNARE proteins
95
What are the SNARE proteins? What can block fusion in absence of ca2+?
V-snare - located on the synaptic vesicle, synpatobrevin (inc VAMP1/2)
T-snare - located on the presynaptic terminal, syntaxin, SNAP-25
Without Ca2+ bound, synaptotagmin blocks fusion
96
What does an influx of calcium trigger?
Calcium influx - action potentials trigger a rapid influx of ca2+ through voltage dependent channels
Activates calcium dependent proteins
Fusion: calcium binding to synaptotagmin causes a confirmational change, allowing SNARE
facilitated membrane fusion to occur
Synaptic vesicle neurotransmitter contents are released into the cleft
97
How are synaptic vesicles recovered? What are synaptic vesicles covered in?
Synaptic vesicle membranes are recovered through endocytosis
Synaptic vesicles are coated with endocytic protein clathrin
Membrane bending recovers the synaptic vesicle membrane
Dynamic facilitates scission of the vesicle from in the membrane (activated through GTP - GPP + P hydrolysis)
Clathrin is removed from the vesicles
98
What do toxins target?
Toxins target SNARE proteins to block synaptic neurotransmitter release
99
What are botulinum toxins?
Botulinum Neurotoxins are peptide toxins composed of heavy and light chains, dervided from Clostridium botulinum.
100
How do BoNTs operate?
BoNTs bind synaptic temrinals of acetyl-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 SNAP25 results in failure of transmitter vesicles to fuse at the synaptic terminal.
Has therapeutic application beyond cosmetics, treatment of epileptic seizures and muscle spasms
101
What are tetanus toxins and how do they operate?
* Tetanus Toxin 9tetanospasmin) are peptide toxins derived from Clostridum tetani
* Tetanus toxin binds pre-synaptic membrane glycoproteins/lipids in neuromuscular junctions and enters motor neurons through endocytosis
* Tetanus toxin is transported to the central nervous system and released into the synaptic clefts, where it is internalised by inhibitory inter neurons
* Tetanus toxins access the presynaptic membrane, then binds and cleaves synaptobrevins VAMP1/2
* Loss of regulatory GABA release results in overactivity of motor neurons and powerful damaging muscle spasms
102
How are synaptic vesicles recovered and refilled?
Recovered synaptic vesicles are acidified by active pumping of H+ into their lumen by vesicular proton ATPases (vATPase)
The acidified lumen then exchanges H+ for neurotransmitters via specific vesicular transports
103
What is VGLUT
VGLUT - vesicular glutamate transporter
104
What is VMAT?
VMAT - vesicular monoamine transporter (serotonin, dopamine, adrenaline, noradrenaline, histamine
105
What is VAchT?
vesicular acetylcholine transporter
106
What is VGAT?
vesicular GABA transporter
107
How are neurotransmitters synthesised? The 2 processes?
* neurotransmitters are produced through enzymatic metabolism of precursors
- small amino acids neurotransmitters
- large neuropeptide transmitters
108
How are small amino acid neurotransmitters produced?
* Small amino acid neurotransmitters - enzymatic processing occurs in the cytosol (cell body or presynaptic terminal) - transmitters are packaged into synaptic vesicles
109
How are large neuropeptide transmitters produced?
* Large neuropeptide transmitters - produced as pre-peptides in the soma ER-Golgi, packaged into dense- core vesicles, transported to presynaptic terminal for processing and secretion
110
What is glutamate? Transporter? Clearance?
Glutamate is the most common excitatory neurotransmitter in mammalian CNS
* metabolised by cytosolic Glutaminase enzyme from precursor glutamine
* Glutamate is loaded into synaptic vesciles by VGLUT transporter
* After release, glutamate is cleared from the synaptic cleft can be neuronal and astroglial
glutamate transporters
111
What is the fate of glutamate in neurons?
Neurons - glutamate return to metabolic pool or reloaded into synaptic vesicles
112
What is the fate of glutamate in astrocytes?
glutamate converted to glutamine by glutamine synthetases. Secreted from astrocytes and taken up by neuronal glutamine transporters
113
What is GABA? Transporter? Clearance?
* GABA is the most common inhibitory neurotransmitter in mammalian CNS
* GABA is synthesised from glutamate by glutamic acid decarboxylase (GAD)
(Both glutamate and GABA are produced from alpha-ketoglutarate, a produce of the mitochondrial kerbs cycle)
* GABA is loaded into synaptic vesicles by vesicular GABA transporter (VGAT)
* After release, GABA is cleared from the synaptic cleft be neuronal and astroglial GABA transporters
114
What is the fate of GABA in neurons?
GABA return to metabolic pool or reloaded into synaptic vesicles
115
What is the fate of GABA in astrocytes?
GABA converted to glutamine and enters the glycine processing pathway to return to neurons
116
What are the 2 types of post synaptic transmission?
Fast transmission
Slow transmission
117
What is fast post-synaptic transmission?
Ligand gated ion channels induce changes in post synaptic membrane potential in milliseconds
118
What is slow post synaptic transmission?
Metabotropic receptors coupled to secondary messengers
- slower (milliseconds-minutes) and long lasting (minutes-days) changes
119
What are the 2 types of fast transmission?
EPSPs
IPSPs
120
What are EPSPs?
Excitatory post synaptic potentials
- ionotrophic receptor allow influx of Na+, K+ and Ca+
- causes membrane depolarisation
121
What are IPSPs?
Inhibitory post synaptic potentials
- ionotrophic receptor allows influx of Cl-
- reduced change of membrane reaching threshold
122
What is the Cys-loop family?
- a category of ligand gated ion channels
- ionotrophic channels including those for acetylcholine, GABA, glycine and serotonin
- all cys-loop receptors are pentamers of subunits forming a pore
- combinations of alpha, beta, gamma and delta subunits defines channel activity (physiological function, pharmacology)
123
How can we actually see what channels look like?
Advanced cryo electron microscopy
- big and expensive
124
What are GABA(A) receptor specialisations?
- ionotrophic channels GABA(A) are selective for Cl- and generally associated with inhibition
- requires binding of 2 GABA molecules to open channel
- pentameric composition of subunits - combination of alpha, beta, gamma and delta subunits determines function (11 different combinations)
125
How is GABA(A) targeted pharmaceutically? GABA(A) alpha 1/2? Inverse agonists?
- GABA(A) receptors are targeted by endogenous molecules and drugs
- Benzodiazepines are agonists for GABA receptors, binding ‘BZ’ site and potentiate Cl- influx
GABA(A) containing Alpha 1 = sedative, anti-convulsive
GABA(A) containing Alpha 2 = anti-anxiety, muscle relaxant
Inverse agonists BZ site and inhibit channel opening, blocking Cl- influx
Axiogenic - ie increase anxiety
Endozepines - endogenous peptide derived from astrocytes
126
What is the glutamate receptor family?
Ionotrophic channels for glutamate, non-selective cations (K+, Na+, Cl2+)
3 categories of glutamate receptors defined by selective inhibitors, all are tetrameric
127
What are the 3 categories of glutamate receptors?
AMPA - alpha-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (GluR1,2,3,4)
GluR2 = responsible for voltage gating, does have Ca2+ selectivity
Kainate - GluR5, GluR6, GluR7 (function less well described, more limited distribution)
NMDA - N-methyl-D-aspartate
128
What are the NMDA receptor specialisations?
NMDA - N-methyl-D-aspartate
- heterotetramer of NR1 (8 isoforms), NR2 (4 isomers)
NR3 confers inhibitory activity
NMDA receptors are voltage gated
- MG2+ ions block the NMDA receptor channel at resting potential
- the Mg2+ block is removed by membrane depolarisation
129
What are NMDA receptors potentiated by? How can NMDA receptors be blocked? Pharmaceutical value?
NMDA receptor activity can be potentiated by binding of co-agonists D-serine and glycine
NMDA receptors can be blocked by Zn2+ and antagonised by Pb2+
NMDA receptors are targeted by dissociative anaesthetics including ketamine, NO and opiates
130
Why are NMDA receptors more suited to being secondary messengers? Role?
NMDA receptors are permeable to Ca2+, allowing longer term activation of secondary messengers
Roles in long term potentiation and long term depression through modulation of AMPA receptor activity
131
What are metabotrophic receptors ?
- activated by neurotransmitters, but not ion channels
- slower response due to indirect activation of ion channels
- activation of metabotrophic receptors lead to a down stream signaling cascade
- excitatory or inhibitory effects on neuronal activity
- more profound, long term effects on neuronal function and morphology
132
How can we learn to ignore a harmless stimulus?
Habituation
Homosynaptic depression : reduced activity within the pathway - ie not requiring a modifying cell
133
Difference between short and long term habituation in depressed action potentials in aplysia?
Depressed synaptic potentials can persist for several weeks post-habituation
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
134
What is sensitisation?
Learning to avoid a noxious stimulus
Dishabitutuation: overcoming a habituated response lasts several
135
What is facilitation?
Increased strength of post synaptic potential to a stimulus if closely paired with a prior stimulus
136
What are the key learning and memory genes that have been identified through genetic screening in drosophilia?
Dunce = cAMP phosphodiesterase (mutation results in elevated cAMP)
Rutabaga = calcium/calmodulin activated adenylyl cyclase, mutation causes slight decrease in cAMP levels
DCO = catalytic subunit of PKA
CREB = transcription factor
137
What does the cAMP signalling pathway do?
CAMP signalling pathway drives habituation and sensitization of neuronal circuits
138
What is heterosynaptic processing?
Synapse activity altered by a modifying neuron
- modulatory inter-neurons release serotonin (5-HT) onto G-coupled 5-HT receptors on presynaptic terminals of send set neurons
139
What is heterosynaptic pathway 1?
- secondary messenger cyclic adenosine mono phosphate produced in presynapse
- activation of cAMP dependent Protein Kinase A (PKA) (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
140
What is heterosynaptic pathway 2?
- enhanced activity of Phospholipase C (PLC)
- increased production of diaglycerol (DAG) activated protein kinase C (PKC)
- phosphorylation of presynaptic proteins increases mobilisation of reserve glutamate vesicles to releasable vesicle pool
141
How long does short term sensitisation increase synaptic release?
Short term sensitisation increases synaptic release for minutes-hours
142
What does long term sensitisation do?
Consolidates short term to long term memory
143
What is the process behind consolidation?
Consolidation: long term sensitisation requires more stable changes in synaptic function and architecture
- sustained activation of 5-HT metabrotopic receptors results in altered gene expression
- activation of CREB regulated genes results in increased production of synapses, changing the morphology of neurons and strengthening its activity
