1 Synaptic Transmission

2 Synaptic contacts Axodendritic – axon to dendrite Axodendritic – axon to dendrite Axosomatic – axon to soma Axosomatic – axon to soma Dendrodendritic – capable of transmission in either direction Dendrodendritic – capable of transmission in either direction Axoaxonal – may be involved in presynaptic inhibition Axoaxonal – may be involved in presynaptic inhibition

3 Structure of the Synapse Synaptic cleft Synaptic vesicles Button microtubules Golgi complex Mitochondrion Dendritic spine Presynaptic membranePostsynaptic membrane

4 Release of Neurotransmitter Exocytosis – the process of neurotransmitter release Exocytosis – the process of neurotransmitter release The arrival of an AP at the terminal opens voltage-activated Ca ++ channels. The arrival of an AP at the terminal opens voltage-activated Ca ++ channels. The entry of Ca ++ causes vesicles to fuse with the terminal membrane and release their contents The entry of Ca ++ causes vesicles to fuse with the terminal membrane and release their contents

5 Ca+ Terminal Button Ca+Exocytosis

6 Neurotransmitter Molecules Two basic categories: Two basic categories: –Small molecule  Synthesized in the terminal button and packaged in synaptic vesicles. –Large molecule (peptide)  Assembled in the cell body on ribosomes, packaged in vesicles, and then transported to the axon terminal.

7 Types of Synapses Directed – the site of neurotransmitter release and receptor activation are in close proximity. Directed – the site of neurotransmitter release and receptor activation are in close proximity. Nondirected – the site of release is at some distance from the site of reception. Nondirected – the site of release is at some distance from the site of reception.

8 Presynaptic activation of ACh muscarinic receptors suppresses synaptic transmission at intrinsic fiber synapses but not at afferent fiber synapses. Postsynaptic activation suppresses normal adaptation of pyramidal cell firing by blocking voltage- and Ca + - dependent K + currents. Combined, these effects may prevent recall of previous memory from interfering with the learning of new memories. (Adapted from Hasselmo, 1995)

9 Receptor-neurotransmitter interactions Released neurotransmitter produces signals in postsynaptic neurons by binding to receptors. Released neurotransmitter produces signals in postsynaptic neurons by binding to receptors. Receptors are specific for a given neurotransmitter. Receptors are specific for a given neurotransmitter. Ligand – a molecule that binds to another. Ligand – a molecule that binds to another. A neurotransmitter is a ligand of its receptor. A neurotransmitter is a ligand of its receptor.

10 Receptors There are multiple receptor subtypes for each neurotransmitter molecule. Two general classes of receptors: 1. Ionotropic receptors – associated with ligand-activated ion channels. 2. Metabotropic receptors – associated with signal proteins and G proteins 1.Postsynaptic 2.Presynaptic (autoreceptors)

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12 Deactivating Neurotransmitters As long as neurotransmitter is in the synapse, it is active – activity must somehow be turned off. 1. Reuptake – neurotransmitter is taken back into the presynaptic terminal. 2. Enzymatic degradation – neurotransmitter is broken down by enzymes.

13 Small-molecule Neurotransmitters Amino acids – the building blocks of proteins Amino acids – the building blocks of proteins Monoamines – all synthesized from a single amino acid Monoamines – all synthesized from a single amino acid Soluble gases Soluble gases Acetylcholine (ACh) – activity terminated by enzymatic degradation Acetylcholine (ACh) – activity terminated by enzymatic degradation

14 Amino Acid Neurotransmitters Usually found at fast-acting directed synapses in the CNS Usually found at fast-acting directed synapses in the CNS Glutamate – Most prevalent excitatory neurotransmitter in the CNS Glutamate – Most prevalent excitatory neurotransmitter in the CNS GABA – GABA – –synthesized from glutamate –Most prevalent inhibitory neurotransmitter in the CNS Aspartate and glycine Aspartate and glycine

15 Monoamines Effects tend to be diffuse Effects tend to be diffuse Catecholamines – synthesized from tyrosine Catecholamines – synthesized from tyrosine –Dopamine –Norepinephrine –Epinephrine Indolamines – synthesized from tryptophan Indolamines – synthesized from tryptophan –Serotonin (5-HT).

16 Acetylcholine and soluble gases Acetylcholine (Ach) Acetylcholine (Ach) –Acetyl group + choline –Neuromuscular junction Soluble gases – exist only briefly Soluble gases – exist only briefly –Nitric oxide and carbon monoxide –Retrograde transmission – backwards communication

17 Ca 2+ Na + Glutamate Polyamine Zn 2+ PCP Mg 2+ Glu Glycine / D-Serine Gly PSD-95 L-Arginine L-Citruline Ca 2+ CaM NO * NOS NMDA Receptor Activation

18 D-serine localization in rat brain

What is the NMDAR System and How Does it Function?  NMDA is a receptor for one of the most prominent excitatory neurotransmitters in the brain (Glutamate)  NMDA Receptors require co- activation of 2 ligands (Glutamate and Glycine)  Ion channel opens allowing Na+ and Ca+ in and K+ out

NMDA Receptor Distribution StriatumHippocampus

21 Pharmacology of Synaptic Transmission Many drugs act to alter neurotransmitter activity Agonists – increase or facilitate activity Agonists – increase or facilitate activity Antagonists – decrease or inhibit activity Antagonists – decrease or inhibit activity A drug may act to alter neurotransmitter activity at any point in its “life cycle” A drug may act to alter neurotransmitter activity at any point in its “life cycle”

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23 Examples of Agonists Cocaine - catecholamine agonist Cocaine - catecholamine agonist –Blocks reuptake – preventing the activity of the neurotransmitter from being “turned off” Benzodiazepines - GABA agonists Benzodiazepines - GABA agonists – Binds to the GABA molecule and increases the binding of GABA

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25 Examples of Antagonists Atropine – ACh antagonist Atropine – ACh antagonist –Binds and blocks muscarinic receptors –Many of these metabotropic receptors are in the brain –High doses disrupt memory Curare - ACh antagonist Curare - ACh antagonist –Bind and blocks nicotinic receptors, the ionotropic receptors at the neuromuscular junction –Causes paralysis

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