Conditions and their neurotransmitter systems Flashcards
What is myasthenia gravis
muscle weakness due to block of ACh at the NMJ
What neurotransmitter system is primarily involved in epilepsy
GABA/glutamate
What is epileptiform activity
overexcitability of a single neuron - may be due to up-regulation of glutamatergic transmission or down-regulation of GABAergic transmission
What is paroxysmal depolarising shift
extended depolarisation at each action potential firing - easier for subsequent action potential firing (similar to activation of NMDA receptor)
What are the 6 possible sites for pharmacological intervention for epilepsy
- Block initiation at the focus
- Block propagation - spread of activity
- Increase GABAergic transmission
- Reduce glutamatergic transmission
- decrease neuronal action potential firing
- Inhibit neurotransmitter release (e.g. calcium channels)
what causes necrosis
sodium and calcium ion influx causes osmotic imbalance, leading to cell lysis and release of cell contents including glutamate and inflammatory mediators
what is primarily responsible for excitoxicity
elevated extracellular glutamate -> persistent neuronal depolarisation
what causes apoptosis
calcium ion influx leads to mitochondria impairment, resulting in decreased ATP, free radical production and release of cytochrome C (an apoptosis initiator)
What is ischaemic stroke
blockage of a cerebral artery
What is haemorrhagic stroke
rupture of cerebral artery
What are the three major processes that occur in ischaemic stroke
- inflammation
- free radical production
- rise in extracellular glutamate concentration
What is used to treat ischaemic stroke and what is its usable time window
Tissue plasminogen activator (TPA) - first 3h
How does TPA help treat ischaemic stroke
converts plasminogen to plasmin which breaks down clots
What does ischaemia lead to
Ischaemia leads to a core in which neurons undergo irreversible necrotic cell death - the core is surrounded by a penumbra of tissue which is susceptible to cell death over a period of 2-3h
Why is targeting glutamate receptors alone in the treatment of stroke a problem
hard to separate the effects of the drugs on abnormal glutamatergic transmission in disorder from effect on receptors required for normal physiological activity
What neurotransmitter system is involved in ALS
glutamate
How is glutamate involved in ALS
selective loss of glial cell glutamate transporter - reduced uptake of glutamate in regions of CNS containing cell bodies of motor neurons
What is ALS
Amyotrophic Lateral Sclerosis: characterised by progressive muscular weakness, leading to paralysis and eventually death
How does genetics affect ALS
superoxide dismutase mutation (SOD1) leads to protein aggregations in motor neurons in the spinal cord
What environmental toxin is a cause of excitotoxic neurodegeneration
domoic acid
What are the effects of domoic acid
atrophied hippocampus
What is domoic acid
Natural product isolated from marine diatoms from west coast USA and Canada and is a potent AMPA/Kainate receptor agonist that can cross the BBB - causes neuronal cell death
What are the major causes of epilepsy
birth and perinatal injuries
congenital malformations
genetic
vascular insults
head trauma
chronic drug/alcohol abuse
neoplasia
infection
idiopathic
What are some seizure triggers
altered blood glucose and pH
stress
fatigue
flashing lights and noise
no apparent cause
What are the categorisations of seizures
simple - no loss of consciousness
complex - impairment of consciousness/awareness
What are partialised seizures
involves one hemisphere of the brain
- may affect movement, sensory experience, mood and behaviour
- temporal lobe - may get stereotypic movements and strong emotional responses
What is ‘Jacksonian epilepsy’
in motor cortex: repetitive jerky movements on one side which spreads
What are the 5 types of generalised seizures
Atonic, tonic, myoclonic, tonic-clonic, absence
What are atonic seizures
loss of muscle tone
What are tonic seizures
increased muscle tone
What are myoclonic seizures
jerking movement
What are tonic-clonic seizures
stiffness and jerking
What are absence seizures
loss of awareness
How is Alzheimer’s Disease diagnosed
Mini-Mental State Exam
PET/SPECT MRI - changes in brain metabolism/blood flow
Altered CSF tau (high) and beta-amyloid (low) proteins (spinal tap/lumbar puncture)
How is Alzheimer’s disease identified post-mortem
brain atrophy
cerebral ventricles symmetrically dilated
neurofibrillary tangles
senile plaques containing beta-amyloid core
neuronal and synaptic loss
What are the causes of Alzheimer’s Disease
majority idiopathic
small percentage hereditary
- mutations associated with processing of beta-amyloid
- chromosome 21 in particular (and also 1, 10, 14, 19)
- early onset
What are the hypothesised causes of Alzheimer’s Disease pathology
Cholinergic dysfunction
Glutamatergic dysfunction
Amyloid hypothesis
Tau hypothesis
Neuroinflammation
How do beta-amyloid plaques form
Abnormal cleavage of amyloid precursor protein leading to excess amyloid accumulation
What is the role of tau
stabilises microtubules
important for transporting molecules and organelles around neuron
How is tau affected in AD
tau is hyperphosphorylated and dissociates from microtubules, leading to misfolding and aggregation into neurofibrillary tangles
What are the direct mechanisms possibly involved in tau hyperphosphorylation
- upregulation of abberant activation of tau kinases
- down regulation of phosphatases
- mutations
- covalent modifications of tau
- others
What are the indirect mechanisms possibly involved in tau hyperphosphorylation
beta-amyloid-mediated toxicity
oxidative stress
inflammation
others
What are the toxic gains-of-functions due to tau
NFTs made of hyperphosphorylated tau sequester normal tau
NFTs become physical obstacles to the transport of vesicles and other cargoes
How is chromosome 21 associated with AD
APP gene - Down syndrome sufferers carry and extra gene copy and exhibit AD-like disorders by age 40
What is the major AD genetic risk factor
APOE4
What is APOE4
major serum lipoprotein involved in cholesterol metabolism -> leads to excess amyloid buildup in the brain before AD symptoms arise
What are the future strategies for AD therapy
- cholinergics
- reduce beta-amyloid production
- increase beta-amyloid clearance
- stop or reverse plaque formation
- increase cell survival
- cell replacement
- reduce oxidative stress
- neuroimmune modulation
What are strategies for decreasing amyloid peptides
- vaccination therapy
- beta- and gamma- secretase inhibitors
- statins
- clioqionol
- NSAIDS
How do statins help in AD therapy
increases processing of APP by alpha-secretase, leading to decreased production of beta-amyloid peptides
How does clioquinol help in AD therapy
decreases Cu/Zn interaction with beta-amyloid peptides, leading to amyloid plaques being cleared
How do NSAIDS help in AD therapy
modulate the way gamma-secretase cleaves amyloid beta fragments
inhibits the production of AB42 peptide
What are the motor symptoms of Parkinson’s Disease
bradykinesia, Parkinsonian gait, reduced arm swing, rigidity, freezing, postural instability, asymmetric resting tremor
What are some non-motor symptoms of Parkinson’s Disease
Depression, anxiety
upper airway obstruction, abnormalities of ventilatory control
muscular weakness and aches
constipation
forced closure of the eyelids
difficulty speaking, excessive salivation, difficulty swallowing
increased sweating
What is the neuropathological cause of Parkinson’s Disease
Death of neurons in substantia nigra leads to dopamine depletion in the striatum
What is the basal ganglia
a group of nuclei associated with the control of movement
What are the components of the basal ganglia
Globus pallidus (GPe, GPi)
Substantia nigra (SNr, SNc)
Subthalamic nucleus (STN)
Striatum (Caudate nucleus, Putamen)
How does the basal ganglia function
- receives excitatory inputs from across the cortex
- output is inhibitory - acts as a brake on motor function
What is the direct pathway in the basal ganglia circuit diagram for motor control
activation of D1 receptors inhibit GPi -> thalamus is disinhibited -> more movement
What is the indirect pathway in the basal ganglia circuit diagram for motor control
D2 receptor -> inhibition of GPe -> inhibition of STN (more excitable) -> excites GPi -> reduces movement
How does Parkinson’s Disease affect the pathways in the basal ganglia circuit
indirect > direct -> less movement
What are the neuronal changes in Parkinson’s Disease
dopamine depletion in the striatum due to neurodegeneration of dopaminergic neurons
formation of Lewy bodies (inclusions containing alpha-synuclein)
What genes are associated with Parkinson’s Disease
PARK 1/4
PARK 3 and 15
PINK1 and LRRK2
How does PARK 1/4 affect Parkinson’s Disease patients
encodes alpha-synuclein
How does PARK 3 and 5 affect Parkinson’s Disease patients
associated with Lewy body formation
How does PINK1 and LRRK2 affect Parkinson’s Disease patients
encode serine/threonine kinase proteins, localised to mitochondria
What are the 4 categories of treatment options for Parkinson’s Disease
- Preventative
- Symptomatic
- Non-motor management
- Restorative (still under clinical trials)
What are the symptoms of Huntington’s Disease
chorea/uncontrollable movements, unsteadiness of gait, difficulty in eating, swallowing, walking, dementia, anxiety, depression, mania
What is Huntington’s Disease caused by
mutation of huntingtin (Htt) gene
What is the pathology of Huntington’s disease
Neurodegenerative, leading to shrinkage and thinning of cerebral cortex
striatum grossly atrophied early
major loss of GABAergic medium spiny interneurons -> reduced activation of indirect pathway
How do mHtt genes differ from normal Htt genes
mHtt contains an expansion of glutamine (CAG) repeats
Why is mHtt pathology restricted to medium spiny interneurons
mHtt binds to the small GTP binding protein Rhes which is selectively expressed in MSNs
What diseases are associated with CAG expansion repeats
Huntington’s Disease
Spinobulbar muscular atrophy
Dentatorubral-pallidouysian atrophy
Spinocerebellar ataxias
How do mHtt inclusions form
Extra long and sticky glutamine sequence -> propensity to create extra H bonds -> misfolding of fragment -> aggregate and go out of solution
What are toxic effects of mHtt inclusions
transcriptional alteration
metabolic dysfunction
proteasome impairment
stress response abnormalities
What are the potential targets for causes of polyglutamine diseases
genetically reduce mHtt expression
protease inhibition
native conformation stabilisation
aggregation inhibition
reversing cellular defects (by promoting neuronal cell health)
How can mHtt expression be reduced genetically
CRISPR Cas9 to remove some glutamine to <35
RNAi bind mHtt mRNA leading to degradation
Antisense oligonucleotides (ASOs) - synthetic DNA strands complimentary to pre-mRNA stopping translation
How does RNAi cross the BBB
viral vector
What is RDoC
Research Domain Criteria - symptoms-based classification of psychiatric disorders recognising overlap between conditions and need to target treatments to specific domains
What are the five categories in the RDoC
negative valence
positive valence
cognitive
social
arousal & regulation
What are the possible causes of pathological anxiety
- brain regions responsible for fear response not shut down (inhibited)
- disruption of serotonergic (5-HT) system which also provides inhibitory inputs to NA system
- disruption of the NA system (arousal)
What are the different types of anxiety
General anxiety disorder
social anxiety disorder
phobias
panic disorder
post-traumatic stress disorder
obsessive compulsive disorder
body dysmorphic disorder
What receptors are involved in the 5-HT brake
presynaptic alpha2 autoreceptor
postsynaptic alpha2 heteroreceptor
What receptors are involved in the 5-HT accelerator
alpha1 receptor
presynaptic alpha 2 autoreceptor
How does increased synaptic [monoamine] cause increased anxiety
activation of somatodentritic autoreceptors (5-HT1A, alpha2 adrenoceptors) -> decreased neuronal firing
activation of presynaptic autoreceptors (5-HT1B/D, alpha2 adrenoceptors) -> decreased neurotransmitter release
What symptoms of schizophrenia are primary targets for drug treatment
delusions
hallucinations
disorganised thoughts
abnormal behaviours
What are some symptoms of schizophrenia which could be worsened by antipsychotics
blunted emotions
anhedonia
poverty of speech
attention impairment
loss of motivation
new learning
memory
executive function
depression
anxiety
impulse control
What are symptoms of muscarinic acetylcholine receptor activation
dry mouth, blurred vision, constipation
What are symptoms of histamine receptor activation
sedative
What are symptoms of adrenergic alpha receptor activation
postural hypotension
What are side effects of 5-HT2A receptor activation
agonists -> propsychotic effects
What are side effects of 5-HT2C
metabolic effects
What are the neurochemical theories in schizophrenia
- Hyperdopaminergic dysfunction
- Serotonergic dysfunction
- Glutamate hypofunction
How are dopamine receptors involved in schizophrenia
Amphetamine-induced DA release can cause acute psychoses
How is serotonin involved in schizophrenia
Drugs which block 5-HT2 receptor exhibit clinical efficacy
5-HT2A agonists induce hallucinations
5-HT2 receptors modulate glutamate and dopamine level
How is glutamate involved in schizophrenia
NMDA antagonists induce psychotic symptoms
What is the hypothesis behind ADHD
dysregulation between cortical and sub-cortical neurotransmission
How do 5-HT and DA interact
Raphe innervation of substantia nigra
5-HT2 modulation of DA in nucleus accumbens
How do NA and 5-HT interact
LC innervation of raphe numbers (alpha1)
NA inhibition (alpha2) at 5-HT terminals
What are the important brain neurotransmitters involved in addiction
dopamine
glutamate
serotonin
What is the reward pathway
Ventral Tegmental Area (VTA) to Nucleus Accumbens
Increased dopamine release in response to positive outcomes
What receptors/transporters do drugs of abuse act on
Dopamine transporter
NA transporter
5-HT transporter, 5-HT2A receptor
NMDA receptor
nicotinic ACh receptor
A1, A2A, A2B and A3 adenosine receptors
CB1 receptor
How does the mu opioid receptor affect dopamine
activation inhibits the GABAergic inhibitory interneurone -> disinhibition increases dopamine release at dopaminergic neurone in VTA
