Neurochemistry Flashcards
What are ependymal cells?
Cells that line the ventricles
They produce, monitor, and circulate CSF
What type of cell is an olfactory or retinal cell?
Bipolar neuron
What are basket cells?
Inhibitory interneurons that form dense plexus of terminals around the soma of target cells
Found in the cerebellum and cortex
What are betz cells?
Large motor neurons
What type of cell forms most of the corpus striatum?
Medium spiny neurons
What are Purkinje cells?
Huge neurons in the cerebellum
What are Renshaw cells?
Neurons with both ends linked to alpha motor neurons
What are granule cells?
The smallest type of neurons, found in the cerebellum
What are anterior horn cells?
Motor neurons located in the spinal cord
What are spindle cells?
Interneurons that connect widely separated areas of brain
What are the main types of circuits neurons can form?
▪️Divergence (same or multiple pathways)
▪️Convergence (single or multiple sources)
▪️Reverberating circuit
▪️Parallel after-discharge circuit
How are neurotransmitters transported down an axon?
I’m vesicles
What evokes the release of neurotransmitters from vesicles?
Influx of calcium caused by action potential
Where do vesicles go after releasing neurotransmitters?
Back up the axon to the soma
What are the two types of axonal transport?
▪️Slow (1-5mm/day)
▪️Fast (200-400mm/day)
What is transported via fast axonal transport?
▪️Neurotransmitters
▪️Growth factors
▪️Toxins/pathogens (e.g. HSV, tetanus)
What is slow axonal transport important for?
▪️Transporting complex products (e.g. axoplasm to terminals)
▪️Neuronal growth
▪️Part of mature neuron function
What are the 3 main types of synapses?
▪️Axodendritic
▪️Axosomatic
▪️Axoaxonic
What targets are relevant for neurotransmitters?
▪️Receptors (ionotropic, metabotropic)
▪️Enzymes
▪️Transporters
▪️Nuclear/mitochondrial receptors
What are ionotropic receptors?
Receptors with a channel that opens up when a ligand (NT) binds to it, changing its shape, and allowing ions to flow across the membrane.
(Aka neurotransmitter-gated or ligan-gated channels)
What are cations?
Ions with a positive charge (e.g., Na+, K+, Ca+)
How does the opening of an ionotropic receptor effect the membrane?
Has direct and fast effects of neural membrane excitability.
How does synaptic transmission with metabotropic receptors compare to ionotropic receptors?
Much slower
What happens when a neurotransmitter binds to a metabotropic receptor?
▪️ G-protein coupled with the receptor is activated and produces effector
▪️ Effector stimulates secondary messenger synthesis
▪️ Secondary messenger activates intercellular process, which opens the channel
What pathways can be activated by G-proteins (GPCR/7TM)?
▪️ Canonical pathway (which activates cyclic AMP or phosphatidylinositol pathway)
▪️ Alternative pathways (via beta-arrestins, GRKs and SrcKs)
Why might different molecules activating the same metabotropic receptor lead to different effects?
Depends on which pathway is activated (show bias for different ones)
What can control metabotropic receptor activity?
G-protein coupling
G-protein coupling has a _________________________
Dynamic equilibrium (at any one time some will be coupled and some wont, changes very quickly)
Which metabotropic receptors do agonists show higher affinity for?
G-coupled receptors (compared to uncoupled)
How does the affinity of antagonists at metabotropic receptors differ when it is G-coupled compared to when it is uncoupled?
No difference
What happens with chronic agonist stimulation of a metabotropic receptor?
Desensitisation - internalisation of receptors, some get destroyed, some get recycled but regeneration of new ones cannot keep up with the number destroyed so total amount reduces
What happens with chronic antagonist stimulation of a metabotropic receptor?
Hypersensitisation - prevents internalisation and destruction of receptors, leading to increased number of receptors on the surface
(Reaction to less stimulation to try and increase stimulation!)
What controls second messenger cellular concentrations?
Specific enzyme pathways (e.g., cyclic nucleotides)
What happens if there is too much secondary messenger?
Increase affinity of the breakdown enzyme for its substrate to increase the breakdown of the messenger
How might one metabotropic receptor interact with another?
Secondary messengers provide a path between them so activity of one can modulate activity of another
What is an excitatory neurotransmitter?
One that enhances the probability of an action potential
Depolarises or increased probability of depolarisation
What is an inhibitory neurotransmitter
Hyperpolarises the membrane and reduces probability of action potential
Can the same neurotransmitter have both excitatory and inhibitory effecrs?
Yes! - depending on the circuit and the receptor it binds to
What controls neurotransmitter release?
▪️ Activity (e.g., change in neuronal firing rate modulated by somatodendritic auto-receptors)
▪️ Synaptic neurotransmitter concentration
▪️ Other neurotransmitters released from other terminals that activate pre-synaptic hetero-receptors
What modulates synaptic membrane excitability and local neurotransmitter release?
Pre-synaptic auto-receptors
What terminates neurotransmitter activity?
▪️ Dissociation of NT from receptor
▪️ Receptor internalisation (typically in response to agonist binding for metabotropic receptors)
▪️ Synaptic “free” NT concentration drops
What causes synaptic “free” NT concentration to drop?
▪️ NT diffuses away
▪️ Re-uptake into pre-synaptic terminal or glia via re-uptake transporters
▪️ Catabolism by extracellular (e.g., acetylcholinesterase, COMT) or intracellular enzymes (e.g., MAO)
What are the main modulatory monoamines?
▪️ Dopamine
▪️ Noradrenaline
▪️ Histamine
▪️ Serotonin (5-HT)
What type of molecule is glutamate, GABA, and glycine?
Amino acids
What constitutes the majority of neurotransmitters in the brain?
Glutamate and GABA
What is GABA?
▪️ Principle inhibitory NT
▪️ Typically acts on ionotropic receptors attached to chloride channels
▪️ Increase of chloride ions = increasingly negative potential (hyperpolarisation)
What is glutamate?
▪️ Principle excitatory NT
▪️ Typically acts on receptors coupled with cation channels - depolarisation!
What is glutamate involved in?
Cognition, memory, and learning
What are the main glutamatergic ionotropic receptors?
NMDA, AMPA, and kainate
What role does glutamate play in neurodegenerative disease?
Insult to brain = increased glutamate release = excitotoxicity = cells self-destruct
What are the most prominent glutamate pathways?
▪️ Cortico-cortical
▪️ Thalamo-cortical
▪️ Cortico-striatal
(also pathways been cortex, substantia nigra, subthalamic nucleus, and pallidum)
What does GABA regulate?
▪️ Neuronal excitability
▪️ Muscle tone
▪️ Levels of alertness
What are the two main types of GABA receptors?
▪️ GABA a = ionotropic (opens Cl- and K+ channels)
▪️ GABA b = metabotropic (works via GPCRs)
Where is GABA taken into and what is it converted to?
▪️ Astrocytes
▪️ Converted into glutamate and glutamine
What happens to glutamine when it is released by astrocytes?
▪️ Taken up by neurons
▪️ Converted into glutamate and then GABA
What are the two acetylcholine receptors?
▪️ Nicotinic (typically excitatory)
▪️ Muscarinic (either excitatory or inhibitory)
What is the main role of acetylcholine?
Cognitive function - possible role in AD/AD treatment
What is the monoamine synthetic pathway?
- L-tyrosine
- L-DOPA
- Dopamine
- Noradrenaline
- Adrenaline
Where are the cell bodies for dopamine synthesis?
Midbrain nuclei - substantia nigra, ventral tegmental area
What are the main functions of D1 and D5 receptors?
▪️ Excitatory
▪️ Increase cAMP which enhances cation channel opening
What are the main functions of D2, D3, and D4?
▪️ Inhibitory
▪️ Decrease cAMP
How many dopamine receptors are there and what kind of receptor are they all?
▪️ 5
▪️ All GPCRs (metabotropic)
How is dopamine taken back into presynaptic terminals and what can inhibit this?
▪️ Via dopamine transporters (DAT)
▪️ Inhibited by amphetamine, cocaine, and methylphenidate - increase reward!
How are dopamine and noradrenaline catabolised?
▪️ By MAO-A in the neurons
▪️ By MAO-B in glial
▪️ By COMT extracellularly
What conditions are associated with abnormal dopamine?
▪️ Schizophrenia (increased in PFC)
▪️ ADHD (decreased)
▪️ Parkinson’s (severe deficiency due to cell death in substantia nigra)
Why is Parkinson’s treated with L-DOPA instead of dopamine?
Dopamine cannot cross the BBB and has severe adverse cardiac effects
Where is noradrenaline synthesised?
Noradrenergic neurons in locus coeruleus
Where does noradrenaline take effect?
▪️ Brain stem
▪️ Spinal cord
▪️ Cerebellum
▪️ Hypothalamus
▪️ Amygdala
▪️ Neocortex
What are the two types of CNS noradrenaline receptors?
▪️ Alpha-2 = inhibitory
▪️ Beta-2 = excitatory
Where else are noradrenaline receptors typically found?
On vasculature
How are dopamine, noradrenaline, and serotonin transported?
In synaptic vesicles by vesicular monoamine transporter (VMAT)
What is the main role of adrenaline?
Attention and focus
What conditions have been associated with abnormal noradrenaline in the brain?
▪️ ADHD
▪️ Depression
▪️ Schizophrenia
What is serotonin derived from?
Tryptophan
What neurons are modulated by serotonin?
Glutamatergic and GABAnergic
Where are serotonergic cell bodies found?
Raphe nuceli
How many receptors are associated with serotonin?
17
What type of receptor are serotonin receptors?
All metabotropic (GPCRs) except for 5-HT3 which is a ligand-gated ion channel
How is serotonin taken back into pre-synaptic terminals?
Via serotonin transporters (SERT)
What inhibits serotonin reuptake?
▪️ MDMA
▪️ Amphetamine
▪️ Cocaine
▪️ Tricyclic antidepressants
▪️ SSRIs
How is serotonin catabolised?
By MAO-A
What role does serotonin play physiologically?
▪️ Well-being
▪️ Happiness
▪️ Mood
▪️ Appetite
▪️ Sleep
What conditions have been associated with abnormal levels of serotonin?
▪️ Depression
▪️ Anxiety
▪️ Eating disorder
▪️ Parkinson’s disease?
What are the main histamine receptors in the CNS?
H1 and H3 (all metabotropic)
How is histamine formed and where?
▪️ By decarboxylation of L-histidine
▪️ In the tuberomammillary nuclei in posterior hypothalamus
What is physiological role of histamine?
Regulation of sleep, appetite, and body temperature
What conditions have been associated with abnormal histamine levels?
Schizophrenia
What are the main purines in the brain?
Adenosine and ATP
What is the main role of adenosine receptors?
Co-localise with other receptors, such as D2, affecting their function
What can block adenosine 2A receptors and what is the effect of this?
Caffeine - decreases function of D2 thus increases the effect of dopamine
What do endorphins do?
▪️ Generally inhibitory
▪️ Act via opioid receptors
▪️ General pain control and feelings of happiness
How are endocannabinoids transported through the cytoplasm?
Via endocannabinoid transporter proteins (eCBTs) because they are very hydrophobic
E.g., heat shock proteins, fatty acid binding proteins
What are the two main endocannabinoids?
▪️ Anandamide
▪️ 2-Arachidonoylglycerol
What are the two main cannabinoid receptors?
▪️ CB1 - one of the most abundant of all CNS receptors
▪️ CB2 - mainly on activated glia, role in immune activation?
How are cannabinoids broken down?
▪️ Fatty acid amide hydrolase (FAAH)
▪️ Monoacyl glycerol lipase (MAGL)
What are the main physiological roles of cannabinoids?
▪️ Feeding behaviour
▪️ Motivation
▪️ Pleasure
What is the Hebbian theory of neuronal plasticity?
Circuits that get used often will be reinforced, making it easier for those cells to communicate
Conversely, connections used less often will die off
What is long-term potentiation?
Persistent strengthening of synapses:
▪️ Strong depolarisation leads to removal of NMDAR Mg2+ block
▪️ Rapid flow of Ca2+ into the cell
▪️ Activation of protein kinases
▪️ Trigger insertion into postsynaptic membrane
What is the cellular basis of synaptic plasticity?
▪️ At resting potential, ion flow through NMDAR is blocked by extracellular Mg2+
▪️ Mg2+ is displaced by depolarisation of post-synaptic membrane
▪️ Pattern of this and presynaptic glutamate release determines extent of NMDAR activation and Ca2+ influx
▪️ Ca2+ activates second messenger pathways
▪️ Pathways enable easier activation of pathway with lower amounts of glutamate
What is long-term depression?
Synapses become less efficient
▪️ Weka depolarisation leads to lesser degree of removal of NMDAR Mg2+ block
▪️ Modest increase in Ca2+
▪️ Activation of protein phosphatases
▪️ Trigger removal from postsynaptic membrane
How is the best way to measure in vivo neurochemistry?
▪️ PET
▪️ SPECT
What is SV2A used for?
A marker of synapses, giving a measure of synaptic density
