Synapse

• Gaps Between Neurons

A synapse is a specialised junction between 2 neurones where the nerve impulse is passed from one neuron to another Santiago Ramón Camillo Golgi y Cajal The Nobel Prize in Physiology or Medicine 1906 was awarded jointly to Camillo Golgi and Santiago Ramón y Cajal "in recognition of their work on the structure of the nervous system Reticular vs Neuronal Doctrine The 1930 s and 1940s was a time of controversy between proponents of chemical and electrical theories of synaptic transmission. Henry Dale was a pharmacologist and a principal advocate of chemical transmission. His most prominent adversary was the neurophysiologist, JohnEccles. Otto Loewi, MD Nobel Laureate (1936) Types of Synapses

• Synapses are divided into 2 groups based on zones of apposition: • Electrical • Chemical – Fast Chemical – Modulating (slow) Chemical Gap-junction Channels

• Connect communicating cells at an electrical synapse • Consist of a pair of cylinders (connexons) – one in presynaptic cell, one in post – each cylinder made of 6 protein subunits – cylinders meet in the gap between the two cell membranes • Gap junctions serve to synchronize the activity of a set of neurons Electrical synapse Electrical Synapses

• Common in invertebrate neurons involved with important reflex circuits. • Common in adult mammalian neurons, and in many other body tissues such as heart muscle cells. • Current generated by the action potential in pre-synaptic neuron flows through the gap junction channel into the next neuron • Send simple depolarizing signals • May transmit metabolic signals between cells Properties of the Electrical Synapse • Two cell membranes are aligned parallel • The synaptic cleft is small ~3.5 nm • Usually between large presynaptic neuron & small postsynaptic neuron – takes a lot of current to depolarize a cell • Specialized proteins called connexons span the pair of membranes to make a very large pore (the Gap Junction Channel) • Signal can be bi-directional Synchronizing Cells • Electrical transmission allows rapid, synchronous firing of interconnected cells – Can interconnect groups of neurons • Very fast; virtually no delay – Speed important for certain responses - defense • Electrically coupled cells can trigger explosive, all or none behavior • Adaptive advantage (e.g. goldfish tail, squid ink) Modulating Conductance • Gap junctions close in response to lower cytoplasmic pH or increased Ca+2 • Some act as rectifiers – channels are sensitive to voltage – therefore transmission unidirectional • Linkage to chemical synapses – neurotransmitters released from nearby chemical synapses can activate 2nd messenger dependent enzymes that alter gating of gap junction channels Mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease and multiple sclerosis.

Class Agents Ions H+, Na+, Ca+, Mg++ Lipophilic agents and fatty acids heptanol, octanol arachidonic acid oleic acid Receptor ligands carbachol (M-cholinoceptor) noradrenaline (α-adrenoceptor) angiotensin-II (AT1 receptor) Cannabinoids Δ9-tetrahydrocannabinol Glycosides strophanthidin, ouabain≈ The Synapse

• Nerve impulses pass from neuron to neuron at synapses, moving from a pre-synaptic neuron to a post- synaptic neuron. Chemical Synapses

• Synaptic cleft is larger • There is no structural continuity between presynaptic & postsynaptic cells • A chemical molecule, a neurotransmitter, is released from the presynaptic neuron – diffuses across the synaptic cleft (20-50 nm) – binds with a receptor on the postsynaptic membrane. Categories of Chemical Synapses • Fast chemical synapses: – Have transmitter-gated ion channels – Fast, electrical response to arrival of presynaptic action potential – Use amino acids and amines as neurotransmitters • Slow, modulatory chemical synapses: – Have G-protein-coupled ion channels – Slow response to arrival of presynaptic action potential – activate second messenger system; not always a direct electrical effect – May use amino acids, amines, or peptides Composition of a Synapse

• The synapse is made of 3 elements: – pre-synaptic terminal – postsynaptic cell – zone of apposition micrography of a synapse What does a synapse look like?

Electron Micrograph

Microscopy with Microscopy with Fluorescent Proteins Fluorescent Proteins

Murthy_HHMI_teachers_2005_sub.ppt Figure 48.12 A chemical synapse Different types of synapse

Synaptic arranjements in the CNS. A.An axodendritic synapse B.An axosomatic synapse C.An axoxonic synapse Properties of the Synapses

First deduced by Sherington Graded Potentials Either Depolarization (Excitation) or Hyperpolerization (Inhibition) of the Postsynaptic Neuron Graded depolarization is known as Excitatory Postsynaptic Potential (ESPS) & occurs when Sodium (Na+) ions enter the postsynaptic neuron or Inhibitory Postsynaptic Potential (IPSP) When Potassium (K+) leaves the cell or chloride enters the cell after stimulation Summation

Temporal Summation Repeated stimulation of one Presynaptic Neuron occurring within a brief period of time that has a cumulative effect on the Postsynaptic Neuron Spatial Summation Several synaptic inputs originating from separate locations exerting a cumulative effect on a postsynaptic neuron Resting Potential

• Resting Membrane Potential High Na+

Low Na+ (RMP): Impermeant anions • 70 mV difference from High K+ + Cell body Axon Axon terminal inside to outside of cell Low K

+ + • It is a polarized + – + – – (a) – + + – + + membrane + – – – – – – – + – – + + – – – – + + • Inside of cell is negative + + + + –70 mV relative to the outside of the cell (b) • RMP = -70 mV + + + – – + – High Na+ – • Due to distribution of ions Low Na+ + + Na + – + + Pump – – – K+ – – – + – – + + + High K + inside vs. outside Low K – – + + + – + + + + • Na /K pump restores –70 mV

(c) Local Potential Changes

Na+ Na+

–62 mV

Chemically-gated Neurotransmitter Na+ channel

Presynaptic neuron (a)

Voltage-gated Na+ channel Trigger zone Na+

Na+ Na+ Na+ Na+

–55 mV

25

(b) Local Potential Changes

Na+ Na+

–62 mV

Chemically-gated Neurotransmitter Na+ channel

Presynaptic neuron (a)

Voltage-gated Na+ channel Trigger zone Na+

Na+ Na+ Na+ Na+

–55 mV

26

(b) Summation of EPSPs and IPSPs

• EPSPs and IPSPs are added together in a process called summation Neuron cell body

• More EPSPs lead to Nucleus greater probability of an Presynaptic action potential knob Presynaptic axon

3927 Action potential Synaptic Transmission

Events at the Synapse Action Potentials cause Calcium to enter the cell leading to the release of Neurotransmitters Released Neurotransmitters attach to Receptor sites altering the activity of the Postsynaptic Neuron Neurotransmitters will separate from their Receptors & are at times converted into Inactive Chemicals Reuptake occurs in some cells recycling Neurotransmitters In some cells empty Synaptic Vesicles are returned to the cell body Requirements at the synapse

For the synapse to work properly, six basic events need to happen: • Production of the Neurotransmitters – Synaptic vesicles (SV) • Storage of Neurotransmitters – SV • Release of Neurotransmitters • Binding of Neurotransmitters – Lock and key • Generation of a New Action Potential • Removal of Neurotransmitters from the Synapse – reuptake

Types of Neurotransmitters

Amino Acids: Acids containing an amine group Peptides: Chains of amino acids Acetylcholine: A chemical similar to an amino acid Monoamines: Nonacidic neurotransmitters containing an amine group & formed by a metabolic change in an amino acid Purines: Adenosine & several of its derivatives Gasses: Includes nitric oxide & possibly others Characteristics of neurotransmitters

- Must be synthesized in a neuron

- Must be present in axon terminal

- Released in response to stimulation

- When applied exogenously, get a biological effect

- There is some mechanism for removing them from synaptic cleft. Neurotransmitters

Synthesized from Transport of Precursors derived Neurotransmitters Certain Neurotransmitters (e.g. from Food acetylcholine) synthesized in the Phenylalanine & Tyrosine precursors Presynaptic Terminal for the Catecholimines Larger Neurotransmitters synthesized Catecholimines: Dopamine, in the cell body & transported down to Epinephrine, & Norepinephrine the axon terminal Choline is the precursor for Transporting of Neurotransmitters can acetylcholine found in foods containing take hours or days for long axons lecithin Tryptophan is the precursor for serotonin Histidine is the precursor for histamine Neurotransmitter Release

Stored in Synaptic Vesicles Depolarization occurs when Action Potential reaches the Axon Terminal After release, there is diffusion across Synaptic Cleft Brain uses dozens of Neurotransmitters Neurotransmitter Release Effects of Neurotransmitters

Ionotropic Effect Neuromodulators Neurotransmitter attaches to the Mainly peptides, that do not excite or receptor causing the immediate inhibit neurons but alter the effects of opening of an Ion Gate a neurotransmitter Metabotropic Effect Neurotransmitter attaches to a receptor & initiates a cascade of metabolic processes Inactivation & Reuptake

Inactivation Reuptake - Inactivation occurs shortly after - Serotonin & Catecholamines go binding to Postsynaptic Receptors through reuptake after leaving - Acetylcholinesterase breaks down Postsynaptic Receptor Acetylcholine after release from the - Reuptake occurs through receptor specialized proteins called - Rapid series of Action Potentials Transporters can release neurotransmitters - Some Serotonin & Catecholamine faster than a presynaptic cell can molecules converted into inactive synthesize it bringing transmission chemicals by Enzymes to a stop

Drugs’ Affects on Synapses

Antagonist A drug that blocks the effects of Neurotransmitters Agonist A drug that mimics a Neurotransmitter Drugs’ influence Synaptic activity: 1. Alters synthesis of Neurotransmitter 2. Disrupts the Vesicles 3. Increases the release of Neurotransmitter 4. Decreases Reuptake 5. Blocks Neurotransmitter breakdown into an inactive chemical 6. Directly stimulates the blocking of Post- synaptic Receptors Affinity Efficacy Synapses & Personality

Important in Almost All Behavior Variance of Receptor Levels may be a genetic marker of Personality Weak correlations found for certain types of behavior & Dopamine Receptors

D2 Receptor implicated in risky behaviors, D4 Receptor associated with “novelty-seeking personality Three Nobel Prize Winners on Synaptic Transmission

Arvid Carlsson discovered dopamine is a neurotransmitter. Carlsson also found lack of dopamine in the brain of Parkinson patients.

Paul Greengard studied in detail how neurotransmitters carry out their work in the neurons. Dopamine activated a certain protein (DARPP-32), which could change the function of many other proteins.

Eric Kandel proved that learning and memory processes involve a change of form and function of the synapse, increasing its efficiency. This research was on a certain kind of snail, the Sea Slug (Aplysia). With its relatively low number of 20,000 neurons, this snail is suitable for neuron research.