BIOL455 COMPARITIVE NEUROBIOLOGY LECTURE#7 DR. OLLIE HULME! FALL 2010! UBC

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1 BIOL455 COMPARITIVE NEUROBIOLOGY LECTURE#7 DR. OLLIE HULME! FALL 2010! UBC

2 Days: MWF, 12-1, room 201! Same old details! Ollieʼs Office hours:! Fri pm (may change)! room 3308 Biosciences! Lindsayʼs Office hours:! to arrange! Midterm 22 nd Oct in class Check website by Friday for practice papers Now working! (without movies)

3 Cellular overview! Electrical signals ch2! Cellular! Voltage-dependent channels ch3 Systems! Cognitive! Channels + transporters ch4 Synaptic transmission ch5! Neurotransmitters + receptors ch6 Synaptic plasticity ch8

4 Last lecture! Electrical synapses Chemical synapses Neurotransmitters Quantal release from vesicles Role of Ca2+ Receptors Post-synaptic potentials

5 This lecture! Taxonomy Ach Glutamate GABA Dopamine 5HT Norepinephrine Epinephrine Neuropeptides Unconventionals

6 Chemical diversity! 100+ transmitters functional / computational diversity different timescales, spatial distributions specific vs. generalised effects Each differs in synthesis, packaging, release, removal Can be grouped according to chemical similarity, and within those groups there are some regularities in their processing

7 Taxonomy! Small mol. Many possible groupings simplest based on size Neuropeptides

8 Subcategories of small mol!

9 Each neurot has specific receptors Receptor not the transmitter which dictates effect of the transmitter Receptors! Can be many different subtypes of receptor: Ionotropic vs Metabotropic Selective vs non-selective Excitatory vs Inhibitory

10 Ionic receptor subtypes! Subtypes composed of different subunits in different combinations

11 Acetylcholine! First neurot discovered NMJ, Visceral motor system but also operates within brain (less well understood)

12 Acetylcholine metabolism!

synaptic concentrations Irreversible forms used as chemical

13 Cholinesterase inhibitors! inhibit degradation of Ach in the cleft causing increased synaptic concentrations Irreversible forms used as chemical weapons (e.g. Sarin) causes neuromuscular paralysis Reversible forms used in treating Alzheimers (e.g. rivastigmine)

14 Nicotinic ACH! Many post-synaptic action due to binding nachr (named since binds nicotine) Ionotropic non-selective cation channels EPSPs

15 Nicotinic! Since Ach has to bind to both sites need high synaptic conc. Binding site is intimately associated with pore therefore rapid response (e.g faster than metabotropic)

16 Muscarinic Receptors! machr activated by poison from mushroom (amanita muscaria) Metabotropic Mediate most effects of Ach in brain 5 subtypes Exert inhibitory effects on motor system Atropine (bella donna)= antagonist

17 Glutamate! Most widespread neurot nearly all excitatory neurons in brain - 50% of all synapses

18 Glutamate synthesis! non-essential amino acid that cannot cross bbb therefore resynth d locally from glutamine

19 Glutamate subtypes - Ionotropic! Named after agonists that activate them Non-selective cation channels Produce EPSPs

20 NMDA! Unusual and important receptor 5 different forms Targetted by antagonists such as ketamine and PCP

21 NMDA is distinctive in 3 ways! 1. Allows in Ca2+ (as well as Na+ & K+) Ca2+ acts as 2 nd messenger to trigger wide array of possible biochemical cascades with different functions e.g. plasticity 2. Voltage sensitive Binds extracellular Mg2+ which blocks pore when hyperpolarised, unbinds when depolarised(v-gated) 3. Requires Co-agonist Opening of channel requires binding of amino acid glycine

22 NMDA voltage sensitivity! Means Ca2+ influx is dependent on pre-existing depolarisation from other synapses or previous activity at same synapse Activity dependent plasticity

23 AMPA! Ionotropic receptor nonselective cations Permeability to Ca2+ depends on combination of subunits Mediates fast transmission

24 Kainate! Ionotropic receptor nonselective cations Similar to AMPA Not as common nor well understood functionally

25 Timecourse of AMPA + NMDA! Different kinetics (rates of reactions)

26 Metabotropic Glutamate receptors! 3 types Modulate channels indirectly Coupled to intracellular pathways in complex ways Slower post-synaptic responses which either increase or decrease excitability

27 GABA! gamma-aminobutyric acid Most inhibitory n s use GABA (or Glycine) ~30% synapses use GABA (mainly interneurons) Inhibition of degradation exploited by drugs (e.g. GHB) 3 types of receptors 2 ionotropic, 1 metabotropic

28 GABA receptors! Ionotropic inhibitory permeable to Cl- IPSP since reversal potential lower than threshold

29 GABA agonists! Benzodiazipines Alcohol Barbiturates

30 Biogenic amines! Group of 5 1. Dopamine (catecholamine) 2. Norepinephrine (catecholamine) 3. Epinephrine (catecholamine) 4. Histamine 5. Serotonin (5ht) Defects in biogenic amines important in psychiatric disorders + common target for drugs

31 midbrain Dopamine!

32 Dopaminergic system! Generally - motivation, reward, reinforcement (voluntary movement, extraversion, lactation, sexual gratification, sleep, mood, attention, working memory, and learning) Involved in parkinson s disease, schizophrenia, addiction, ADD, mania Cocaine + amphetamine inhibits DAT reuptake transporter Degraded by COMT + MAO enzymes

33 Brain stem Norepinephrine!

34 Norepinephrine! Sleep, arousal, attention, feeding, unexpected uncertainty Closely related to dopamine, made from dopamine, same vesicular transporter, reuptake by NET which also acts on dopamine, degraded by same enzymes COMT and MAO NET transporter inhibited by amphetamines

35 Epinephrine! Less understood Less prevalent Brain stem

36 Histamine! Sparse but global projections Arousal, attention Targetted by anti-histamines hence sedative effects

37 Serotonin! Global diffuse Brain stem

38 Serotonin! Targetted by drugs for depression and anxiety Synth d from amino acid tryptophan (dietry absence can induce depression effects) re-uptake via SERT (SSRI drugs inhibit this transporter) Degraded by MAO enzyme

39 Neuropeptides! Made in soma Processed in ER Packaged into vesicles Proteolytic cleavage Multiple types within vesicle + coreleased with small molecule neurots Catabolised by peptidases on outer membrane surface

40 Neuropeptides 5 classes! Pain anxiety stress Circadian rhythm aggression, blood pressure and temperature regulation Sexual arousal, bonding, love, empathy trust Stress hormone regulation of energy balance, memory and learning,

41 Opioids! Opioid peptides activate same receptors as opium (morphine) 20 types in 3 classes Endorphins - exercise, excitement, pain, orgasm, feelings of well-being Enkephalins pain, analgesia Dynorphins analgesia, stress, temperature, depression, appetite

42 Unconventional neurots! Triggered by Ca2+ but not stored in synaptic vesicles, not released by exocytosis Sometimes drive retrograde signals from post-synaptic to pre-synaptic Endocannabinoids molecular target of THC, neuromodulatory lipids effects appetite, pain-sensation, mood, and memory Nitrous Oxide gaseous transmitter (often classed as 2 nd messenger), anxiolytic, analgesic, euphoric effects

43 Next Lecture! Synaptic plasticity read chapter 8 before friday

Synaptic transmission

Outline Synaptic transmission Sompol Tapechum M.D., Ph.D. Department of Physiology Faculty of Medicine Siriraj Hospital, Bangkok, Thailand. sisth@mahidol.ac.th 2 Structure of synapse Modes of synaptic