Chemical synapses

• Information flow in the nervous system

  Action potentials transmit information within cells

  Chemical transmission from one cell to another occurs at synapses.

  
• Synapses – voltage gated Ca2+ channels

  Open when the membrane depolarises to around -40 to -60 mV.

  Calcium enters the cell

  The calcium then allows for vesicle release at the synapse

  
• Neurotransmitter release


  1. The action potential is transmitted to the presynaptic terminal. Depolarisation spreads over the presynaptic membrane.
  2. The depolarisation leads to the opening of voltage gated calcium channels (VGCC) in the membrane, and calcium flows into the terminal down the concentration and electrical gradients.
  3. The increasing calcium concentration stimulates the release of neurotransmitter into the presynaptic cleft, which diffuses to the postsynaptic membrane.

  
• Vesicle release


  1. Vesicles need SNARE proteins to dock and release.
  2. The vesicle had v-SNAREs and the membrane has t-SNAREs.
  3. The SNARE peptide has a lipophilic region which is inside the membrane, and a long tail which projects into the cytosol.
  4. When these tails bind to each other in the presence of calcium, it allows the vesicle to “dock”.

  
• Vesicle

  
• Various shapes and sizes of CNS synapses

  (a) Axospinous synapse: small presynaptic axon terminal contacts a postsynaptic dendritic spine.

  (b) Axosomatic synapses = axon branches to form two presynaptic terminals, one larger than the other and both contact the postsynaptic soma.

  
• Various shapes and sizes of CNS synapses

  (c) Unusually large axon terminal contacts and surrounds a postsynaptic soma. Shown in Calyx of Held (found where auditory sensory neurons connect to trapezoid nucleus neurons in pons). Necessary for quick transmission of signals from one neuron to the next. AP leads to a new AP in the postsynaptic neuron.

  (d) Unusually large presynaptic axon terminal contacts five postsynaptic dendritic spines.

  
• Lifecycle of neurotransmitters: Synthesis

  1. The NT is created from precursor molecules. These can be made in the soma (slow), at the axon terminal, or come externally

  
• Lifecyle of neurotransmitters: Packaging and storage

  2. NTs are moved into vesicles from early endosomes and await the arrival of an AP

  
• Lifecycle of neurotransmitters: Translocation

  3. Vesicles move in and out of the synaptic bouton

  
• Lifecycle of neurotransmitters: Release

  4. An AP causes the release by exocytosis. This requires the vesicle to dock, prime, and fuse

  
• Lifecycle of neurotransmitters: Receptor activation

  5. The NT binds to receptors in the synaptic cleft

  
• Lifecycle of neurotransmitters: Inactivation

  6. The NT either diffuses away, is enzymatically degraded, is taken by the terminal neuron, or an astrocyte

  
• Neurotransmitter clearance by astrocytes – the tripartite synapse

  • In order to allow for repetitive signalling, the NT in the synaptic cleft needs to be cleared immediately.
  • Astrocytes play a role in NT clearance, and are well known for their glutamate clearance by utilising excitatory amino acid transporters (EAATs).
  • Glutamate transporters in the astrocyte hoover up all of the glutamate. This is then converted to glutamine and sent back to the neurons.

  
• Neurotransmitters and their receptors

  • As neurotransmitters reach the postsynaptic membrane they come across a dense area of receptors in the postsynaptic density.
  • There are many different receptors based on the kind of neuron, its signalling mechanisms, its location and function.

  
• Neurotransmitters and their receptors

  Classical neurotransmitters (NTs):

  • Small (amino acids and amines)
  • Their receptors far outnumber the neurotransmitters.

  
• Neurotransmitter receptors - Ligand-gated ion channels

  Ligand gated ion channels:

  • only activated by specific molecules (NTs).
  • Ligand binding opens the channel.
  • The channels are permeable to different ions.
  • Excitatory receptors allow influx of Na+ and Ca2+ and efflux of K+, while inhibitory receptors are permeable to Cl-.

  
• Excitatory and inhibitory neurotransmission

  Receptor activation within dendrites causes ion flow that generates post-synaptic potentials.

  
• EPSP summation: temporal or spatial

  
• Neuronal transmission- synaptic integration

  • Normally more than one EPSP is needed to raise the membrane potential up enough to generate an action potential
  • IPSPs reduced the likelihood of this happening
  • Summation at the axon hillock only occurs when the membrane potential reaches the threshold is the action potential generated.

  
• Coding information in the nervous system

  Inside cells = frequency of action potentials (digital)

  Between cells = amount of NT release

  
• Synaptic connectivity and function


  Visual processing – extraction of features

  
• Synaptic connectivity and function [i]

  Neuromodulation

  
• Synaptic connectivity and function [II]

  Neuromodulation

  • Dopamine can be excitatory or inhibitory depending on the receptors expressed in the post-synaptic cell
  • Gating of excitatory signals, e.g. by reward expectation

  e.g. response selection in striatum

  
• Global brain circuits

  
• Synaptic connectivity and function: Hippocampus

  • Hippocampus is an association network
  • Cells that fire at the same time become associated – memory formation
  • When some of these cells are reactivated, they can reactivate the whole network – memory recall
  • But can become epileptic

  
• Synaptic plasticity and learning [I]

  • Synaptic conduction can be strengthened or weakened based on past-experience
  • Synaptic plasticity represents forms of learning and memory
  • Both presynaptic and postsynaptic modifications can be involved.
• Synaptic plasticity and learning [I]: Mechanisms examined

  • Changes in amount of neurotransmitter release
  • Biophysical changes to receptors and channels
  • Modulation by other transmitters, proteins or channels
  • Morphological changes to the post-synapse (dendrites and spines)
  • Synapse loss or sprouting
  • Changes in gene transcription
• Synaptic plasticity and learning [II]

  Forming associations – learning

  • Strength of some synapses changes with experience
  • Hebb’s postulate – “cells that fire together, wire together”.
  • Lots of summation = lots of depolarisation – activation of NMDA receptors and calcium entry
  • Calcium triggers processes that make synapses stronger so next time, it is easier for these synapses to make the post-synaptic neuron fire an action potential
  • Opposite can also happen – connections between cells that don’t fire together become weaker

  SYNAPSES CAN BE PLASTIC

  
• Synaptic structure changes that may subserve learning

  
• Synaptic plasticity and learning – change in number of synapses

  • Researchers working with Eric Kandel discovered that the number and size of sensory synapses change in well-trained, habituated or sensitized Aplysia californica.
  • Synapse number is decreased in habituated animals and increased in sensitized animals.

  
• Synaptic plasticity and learning – modulation of second messengers

  They determined the cAMP was important for learning as mutations that either increase or decrease cAMP levels reduce the learning capacity of drosophila.

  
• Neurotransmission in the somatic, autonomic and enteric nervous system

  
• Neurotransmission in the somatic and autonomic nervous system

  
• Neurotransmission in the autonomic nervous system

  • The autonomic nervous system regulates internal functions. i.e. Keeps heart beating, liver releasing glucose, pupils adjusting to the light, etc.
  • Without the ANS, life would quickly cease.
  • Although sometimes it can be possible, conscious control of these things is unnecessary and it must function without conscious control so that it keeps on working during sleep.
  • On the other hand, sometimes conscious states can affect the ANS, such as when you are stressed, this leads to a raised heartbeat, among other things.
• Neurotransmission in the sympathetic nervous system

  • Fight or flight response
  • Constantly active at a basal level of homeostasis

  
• Neurotransmission in the parasympathetic nervous system

  • responsible for stimulation of "rest-and-digest" or "feed and breed“
  • activities at rest, especially after eating, sexual arousal, salivation, lacrimation (tears), urination, digestion and defecation.
  • Involve the cranial nerves, the vagus nerve and pelvic splanchnic nerves.

  
• Organisation of neural outputs in the autonomic nervous system

  
• Neurotransmission in the sympathetic nervous systems

  1. preganglionic neurons release ACh
  2. the postganglionic neurons express nicotinic ACh receptors
  3. stimulation of the postganglionic neurons makes them release norepinephrine which activates adrenergic receptors on peripheral targets.

  OR

  • the adrenal medulla is stimulated to release norepinephrine and epinephrine in the blood system

  
• Neurotransmission in the parasympathetic nervous system

  • Normally, when stimulated, the preganglionic neuron releases ACh at the ganglion, which acts on nicotinic receptors of postganglionic neurons.
  • The postganglionic neuron then releases ACh to stimulate the muscarinic receptors of the target organ.
  • Different muscarinic receptors are expressed by different targets.