Transcript uptake
The Nervous System PART 1: The role of Glia and the Blood Brain Barrier PART 2: The synapse and neurotransmitters Dr Margaret Barnes-Davies Relates to learning outcome 1: Explain how the proper function of the nervous system depends on its anatomical and biochemical integrity Components of the central nervous system • Network of neurones with supporting glia • Neurones sense changes and communicate with other neurones – around 1011 neurones • Glia support, nourish and insulate neurones and remove ‘waste’ – around 1012 glia Types of glial cells (neuroglia) • Astrocytes (several different types) – supporters – most abundant type of glial cell • Oligodendrocytes – insulators • Microglia – Immune response The role of astrocytes • Structural support • Provide nutrition for neurones – glucose-lactate shuttle • Remove neurotransmitters (uptake) – control concentration of neurotransmitters (especially important for glutamate (toxic) • Maintain ionic environment – K+ buffering • Help to form blood brain barrier Astrocytes help provide energy for neurones • Neurones do not store or produce glycogen • Astrocytes produce lactate which can be transferred to neurones •Supplements their supply of glucose • Glucose lactate shuttle Astrocytes help to remove neurotransmitters PRESYNAPTIC TERMINAL GLIAL CELL glutamate glutamate POSTSYNAPTIC DENDRITE UPTAKE Astrocytes have transporters for transmitters such as glutamate. This helps to keep the extracellular concentration low. Astrocytes help to buffer K+ in brain extracellular fluid The Blood Brain Barrier • Limits diffusion of substances from the blood to the brain extracellular fluid • Maintain the correct environment for neurones • Brain capillaries have – tight junctions between endothelial cells – basement membrane surrounding capillary – end feet of astrocyte processes The Blood Brain Barrier Adapted from Abbott et al (2006) Nature Reviews Neuroscience 7:41-53 Pathways across the BBB Substances such as glucose and amino acids and potassium are transported across BBB. Concentration can be controlled Oligodendrocytes • Responsible for myelinating axons in CNS • Compare with PNS where Schwann cells are responsible for myelination • Good time to revise M&R module and myelination Microglia • Immunocompetent cells • Recognise foreign material - activated • Phagocytosis to remove debris and foreign material • Brain’s main defence system CNS: Immune privileged (immune specialised) • Does not undergo rapid rejection of allografts • Rigid skull will not tolerate volume expansion – Too much inflammatory response would be harmful • T-cells can enter the CNS • CNS inhibits the initiation of the proinflammatory T-cell response • Immune privilege is not immune isolation, rather specialisation Introduction to Neurotransmission • How neurones communicate - The synapse – fast excitatory neurotransmission – fast inhibitory neurotransmission – modulatory responses • Examples of neurotransmitter systems Typical neuronal structure dendrites soma dendrites myelin sheath node of Ranvier internode presynaptic terminal axon Four main sections: • cell soma • dendrites • axon • terminals Neurotransmitter release The synapse AP • Depolarisation in the terminal opens voltagegated Ca2+ channels. Ca2+ ions enter the terminal. • Vesicles fuse and release transmitter. receptors dendrite of postsynaptic cell •Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane Postsynaptic response • depends on – nature of transmitter – nature of receptor receptors dendrite of postsynaptic cell • Ligand gated ion channels • G-protein-coupled receptors Neurotransmitters in the CNS • > 30 neurotransmitters have been identified in the CNS • Can be divided into three chemical classes AMINO ACIDS glutamate, GABA, glycine BIOGENIC AMINES acetylcholine, noradrenalin dopamine, serotonin (5-HT), histamine, PEPTIDES From: Bear, Connors & Paradiso Neuroscience: Exploring the Brain dynorphin, enkephalins, substance P, somatostatin cholecystokinin neuropeptide Y Fast Responses Amino acid neurotransmitters acting on ligand-gated ion channels • excitatory amino acids – mainly glutamate – major excitatory neurotransmitter • over 70% of all CNS synapses are glutamatergic • present throughout the CNS • inhibitory amino acids – GABA – Glycine Glutamate receptors Ionotropic AMPA receptors Kainate receptors Metabotropic NMDA receptors mGluR1-7 G protein-coupled receptor Ion channel - permeable to Na+ and K+ (and in some cases Ca2+ ions) Activation causes depolarisation – increased excitability Linked to either: • changes in IP3 and Ca2+ mobilisation • or inhibition of adenylate cyclase and decreased cAMP levels Fast excitatory responses Excitatory neurotransmitters cause depolarisation of the postsynaptic cell by acting on ligand-gated ion channels. -excitatory postsynaptic potential (EPSP) - depolarisation causes more action potentials action potentials EPSP resting membrane potential (RMP) ~ -60mV Glutamate receptors, synaptic plasticity and excitotoxicity • Glutamate receptors are thought to have an important role in learning and memory – Activation of NMDA receptors and mGluRs can lead to upregulation of AMPA receptors – long term potentiation • Ca2+ entry through NMDA receptors is important in excitotoxicity – Too much glutamate - excitotoxicity Inhibitory Amino Acids • GABA is the main inhibitory transmitter in the brain GABA • Glycine acts as an inhibitory neurotransmitter mostly in the brainstem and spinal cord Glycine GABA and Glycine Receptors • GABAA and glycine receptors have integral Cl- channels • Opening the Cl- channel causes Cl hyperpolarisation - Cl- – Inhibitory post-synaptic potential (IPSP) • Decreased action potential firing action potentials IPSP -60mV (resting membrane potential) Also have GABAB G-protein coupled receptors - modulatory role GABA is the main inhibitory neurotransmitter in the brain • Barbiturates and benzodiazepines bind to GABAA receptors • Both enhance the response to GABA – Barbiturates - anxiolytic and sedative actions, but not used for this now • risk of fatal overdose also dependence and tolerance • Sometimes used as anti-epiletic drugs – Benzodiazepines – have sedative and anxiolytic effects – used to treat anxiety, insomnia and epilepsy Glycine is present in high concentration in the spinal cord and brainstem Inhibitory interneurones in the spinal cord release glycine Biogenic amines and acetylcholine • • • • • • acetylcholine dopamine noradrenaline serotonin (5-HT) mostly act as neuromodulators confined to specific pathways Acetylcholine as a neurotransmitter • ACh – neuromuscular junction – ganglion synapse in ANS – postganglionic parasympathetic • ACh is also a central neurotransmitter – acts at both nicotinic and muscarinic receptors in the brain – mainly excitatory – receptors often present on presynaptic terminals to enhance the release of other transmitters Cholinergic pathways in the CNS neurones originate in basal forebrain and brainstem diffuse projections to many parts of cortex and hippocampus also local cholinergic interneurones eg in corpus striatum Cholinergic pathways in the CNS • ACh – widely distributed throughout the brain • muscarinic and nicotinic ACh receptors – mainly excitatory effects • main functions – arousal, learning & memory, motor control • degeneration of cholinergic neurones in the nucleus basalis of Meynert is associated with Alzheimer’s disease • Cholinesterase inhibitors are used to alleviate symptoms of Alzheimer’s disease Dopaminergic pathways in the CNS involved in motor control involved in mood, arousal and reward Conditions associated with dopamine dysfunction • Parkinson’s disease • associated with loss of dopaminergic neurones • substantia nigra input to corpus striatum • can be treated with levodopa - converted to dopamine by DOPA decarboxylase • Schizophrenia • maybe due to release of too much dopamine – amphetamine releases dopamine & noradrenaline – produces schizophrenic like behaviour – antipsychotic drugs are antagonists at dopamine D2 receptors Noradrenaline • noradrenaline - transmitter at postganglionic – effector synapse in ANS • also acts as a neurotransmitter in the CNS • operates through G protein-coupled αand β-adrenoceptors • receptors to noradrenaline in the brain are the same as in the periphery Noradrenergic pathways in the CNS cell bodies of NA containing neurones are located in the brainstem (pons and medulla) diffuse release of NA throughout cortex, hypothalamus, amygdala and cerebellum NA and behavioural arousal • most NA in the brain comes from a group of neurones in the locus ceruleus – LC neurones inactive during sleep – activity increases during behavioural arousal – amphetamines increases release of noradrenaline and dopamine and increase wakefulness • Relationship between mood and state of arousal – depression may be associated with a deficiency of NA Serotonergic pathways in the CNS Serotonin 5-HT - similar distribution to noradrenergic neurones functions – sleep/wakefulness Mood SSRIs (serotonin selective reuptake inhibitors) treatment of depression and anxiety disorders Vomiting centre in brain stem Summary • Astrocytes, oligodendrocytes and microglia have important functions in the CNS • The blood brain barrier ensures that brain extracellular fluid maintains the correct composition • The synaptic response depends on the neurotransmitter released and the receptors it acts on • The main neurotransmitters in the CNS are the amino acid transmitters – glutamate - major excitatory neurotransmitter – GABA and Glycine - major inhibitory neurotransmitters • Other neurotransmitters such as ACh, 5-HT, NA, dopamine and peptides have important modulatory roles • Drugs can be targeted at specific neurotransmitter systems and receptors subtypes to produce CNS effects Pathways across the blood brain barrier Paracellular aqueous pathway Transcellular lipophilic pathway Transport proteins Receptor – mediated endocytosis Adsorptive transcytosis Monoamines – mood, arousal and depression • monoamine theory – depression - due to a functional deficit of monoamine transmitters in some brain areas – mania - due to a functional excess • many drugs used in treatment of mood disorders act on the monoamine pathways – tricyclic antidepressants • inhibit uptake of NA/5-HT – SSRIs (serotonin selective reuptake inhibitors) • treatment of depression and anxiety disorders – MAOIs (monoamine oxidase inhibitors) • MAO – enzyme which metabolises monoamines • antidepressants – prevent breakdown of monoamines within the terminal