L3 - Neurotransmitters Flashcards
Role of glial cells
Support, nourish and insulate neurones whilst also removing waste
Types of glial cells
Astrocytes - most abundant
Microglial cells
Oligodendrocytes
Role of astrocytes
Structural roles Nutritional role - glucose - lactate shuttle Removes excess neurotransmitters Maintain ionic environment - K+ buffer Helps to form the blood brain barrier
Glucose transport into neurones
Directly - from the blood to the neurone through the interstitial space via GLUT1 and GLUT3
Indirectly - via glucose - lactate shuttle using astrocytes
Glucose - lactate shuttle
- Glucose from the blood is taken up by the astrocytes via GLUT1 and converted into glycogen for storage
- When the glucose demand in the neurone is high, glycogenolysis occurs where glycogen is converted to Pyruvate
- Pyruvate is then converted to lactate
- Lactate is transferred to the neurone via MCT1 and 2
- In the neurone, lactate is then converted to pyruvate where it can be used to produce ATP
How do astrocytes remove excess neurotransmitters
Via transporters
Astrocytes are abundant near synapses
Keeps extracellular neurotransmitter concentrations low to avoid exitotoxicity
Astrocyte K+ buffer
High neuronal activity increases ECF K+ concentration in the brain
Astrocytes take up K+ via:
- NKCC2
- Na+/K+ ATPase
- Potassium channels
Cl- channels on astrocytes
Keep intracellular membrane potential in the astrocyte low so more K+ can diffuse in down the concentration gradient
Oligodendrocytes
Myelinated axon in the CNS
Many axons per oligodendrocytes
Microglia cells
- Recognise foreign material and become activated
- Phagocytose
- Antigen presenting cells to T cells
How are microglia cells activated
- Recognise foreign material
- Processes become thicker
- Form active phagocytic form
Blood brain barrier
Controls and limits the diffusion of substances from the blood to the brain ECF to maintain an optimum environment
Formed by endothelial cell tight junction and the basement membrane around capillaries mainly and astrocyte end feet processes partially
High intracellular K+
Causes depolarisation in surrounding neurones which leads to excess glutamate release.
Excess Ca2+ enters the neurone which causes exitotoxicity
What substances are transported across the blood brain barrier?
Free diffusion:
- O2
- CO2
- H2O
Facilitated diffusion:
- glucose
- amino acids
- sodium
- potassium
Immune privilege
- The brain does not undergo rapid rejection of allografts
- CNS inhibits the initiation of the pro-inflammatory T cell response (specialised response)
- prevents increase in intracranial pressure
Structure of a neurone
Cell soma - cell body
Dendrites - where axons synapse onto
Axon - carries action potentials
Presynaptic terminals - where neurotransmitters are released
Axon hillock - where action potential is propagated
Neurotransmitter release in synapses
- Action potential arises at the presynaptic terminal
- Voltage gates Ca2+ channels open allowing an influx of Ca2+
- Vesicles fuse with the presynaptic membrane and release the neurotransmitter
- The neurotransmitter diffuses across the synaptic cleft and bind to specific receptors on the postsynaptic membrane
- Ligand gated channels open allowing an influx of an ion
Factors affecting the postsynaptic response
Type of ligand gated ion channel or GPCR
Type of neurotransmitter
Types of neurotransmitters
Amino acids
Biogenic amines
Peptides
Examples of amino acid neurotransmitters
Glutamate
Glycine
GABA
Examples of biogenic amine neurotransmitters
Acetylcholine Noradrenaline Dopamine Serotonin Histamine
Examples of peptide neurotransmitters
Substance P Somatostatin Cholecystokinin Neuropeptide Y Dynorphin Enkephalins
Excitatory amino acid neurotransmitter
Glutamate - most abundant neurotransmitter (70%)
Inhibitory amino acid neurotransmitters
Glycine - brainstem and spinal cord
GABA - brain
Types of glutamate receptors
Ionotropic
Metabotropic
Ionotropic glutamate receptors
AMPA - Na+/K+
Kainate - Na+/K+
NMDA - Na+/ K+ /Ca2+
- cause depolarisation and increases excitability
Metbotropic receptors
mGluR1-7 GPCR
- G alpha q or G alpha i proteins
Fast excitatory response
- convergence of many synapses increases depolarisation
- excitatory postsynaptic potential
- depolarisation exceeding the threshold level of stimulation causes the propagation of action potentials
Glutamatergic synapses
Have AMPA and NMDA receptors
AMPA receptors
Mediate the initial fast depolarisation
NMDA
Dependent on AMPA for depolarisation as requires glutamate to bind and cell depolarisation to allow ion flow through the channel
Normally inhibited by magnesium
Permeable to Ca2+
Glycine acts as a co - agonist
Silent synapses
Synapses that only have NMDA receptors
Can not function as requires depolarisation by AMPA receptors
Role of glutamate receptors
Learning and memory
- activation of NMDA unregulates AMPA
- strong, high frequency stimulation and Ca2+ entry causes long term potentiation
Stroke
- Ischaemia to part of the brain causing ischaemic necrosis and an infarct
- release of K+ causes depolarisation in neighbouring neurones
- increased glutamate release
- increased Ca2+ influx
- excitotoxicity
GABA and glycine receptors
Have integrated Cl- channels
Opening the channels cause hyperpolarisation
IPSP
Decreased action potential firing
GABA GPCR
Modulators role
Barbiturates
Anxiolytics, antiepileptic and sedative actions
Not used as sedative now due to risk of fatal overdose, dependence and tolerance
Binds to GABA receptors and modulates the activity of GABA
Benzodiazepines
Binds to GABA receptors and modulates activity
Anxiolytic and sedative actions Treats: - insomnia - epilepsy - anxiety
Acetylcholine
Present in:
- neuromuscular junctions
- ganglion synapses in the ANS
- postganglionic parasympathetic neurones
Acts on:
- nicotinic and muscarinic receptors in the brain
Action:
- mainly excitatory
- can enhance the release of other transmitters,
Cholinergic pathways
Role:
- arousal
- learning
- memory
- motor control
Location:
- nucleus basalis
- septal nuclei
- hippocampus
- thalamus
- corpus striatum
Alzheimer’s disease
Involves degeneration of the cholinergic neurones in the nucleus basalis
Alleviation of Alzheimer’s disease symptoms
Cholinesterase inhibitors preventing the degradation of acetylcholine so more is available
Dopaminergic pathways
Mesocortical pathways and mesolimbic pathways:
- mood
- arousal
- reward
Nigrostriatal pathway - involves striatum and substantia nigra
- motor control
Parkinson’s disease
Loss of dopaminergic neurones
Loss of substantia nigra input to the corpus striatum
Lack of dopamine release
Treatment of Parkinson’s disease
Levodopa - converted to dopamine by DOPA decarboxylase
- precursor of dopamine
- passes through the blood brain barrier via large neutral amino acid transporters LNAA
- converted to dopamine in the brain via aromatic amino acid decarboxylase AADC
- Carbidopa is also given to inhibit AADC in the periphery so extra dopamine is not produced in the periphery
Schizophrenia
Release of too much dopamine
- amphetamine releases dopamine and noradrenaline therefore can produce schizophrenic like behaviour
Anti psychotic drugs
Antagonists of the dopamine D2 receptor
Noradrenergic pathways
Cell bodies of noradrenergic neurones are found in the brain stem at the:
- medulla
- pons - locus ceruleus (majority)
- diffuse release of noradrenaline throughout the cortex, hypothalamus, amygdala and cerebellum
- from few neurones spreads widely
Activity of noradrenaline
- inactive during sleep
- increased activity during behaviour arousal
- amphetamines increases release of dopamine and noradrenaline to increase wakefulness
Depression
There is a relationship between mood and the state of arousal
Depression may be associated with the lack of noradrenaline
Serotonergic pathways
Serotonin - similar distribution to neuroadrenaline
Function:
- sleep and wakefulness
- mood
Serotonin selective reputable inhibitors
Treatment of depression and anxiety disorders
Norepinephrine
- Released by the locus coeruleus
- released rostrally
Role:
- sleep
- arousal
Reticular formations project causally for muscle tone
Dopamine
Released by the substantia nigra and spreads via the nigrostriatal pathway
Also released by the ventral tegmentum area
Action:
- mood
- arousal
- reward
Viabthe mesolimbic and mesocortical pathways
Serotonin
Released by the raphe nuclei
Projects rostrally
Action:
- sleep
- mood
Acetylcholine
Released by the basal forebrain nuclei and the pontine nuclei Mostly excitatory Action: - arousal - memory - learning - motor control
