Lecture 29: Synaptic Transmission

Synaptic Transmission

• Synaptic transmission is the process of transferring information between neurons or between neurons and muscle fibers.
• Occurs through:
  • Chemical synapses
  • Electrical synapses (via gap junctions)
• In the developed mammalian brain, synaptic transmission occurs almost entirely through chemical synapses.
• Synaptic transmission between neurons and muscle fibers is also via chemical synapses; these peripheral synapses are called neuromuscular junctions or end plates.

Why Chemical Synapses?

• Depolarization at the presynaptic terminal causes the release of a neurotransmitter, which diffuses across the synaptic cleft and binds to receptors in the postsynaptic membrane.
• Binding usually initiates the opening of a channel associated with the receptor, and a current in the postsynaptic cell.
• Key features of chemical synapses:
  • Specificity: specific neurotransmitters have specific effects on postsynaptic membrane.
  • Complexity: type, time course, strength, location, timing, etc.
  • Plasticity: changes in synaptic structure and function associated with development, aging, learning etc.

Neurotransmitters

• Chemical 'messengers' that open (or sometimes close) ion channels, leading to depolarization or hyperpolarization of postsynaptic membrane.
• At least 50 substances are known, or are strongly suspected, to act as neurotransmitters (or 'neuromodulators') in the brain or in the PNS.
• Each neurotransmitter can bind to many different types of receptors, with each receptor producing a different effect on neuron function.
• The diversity of neurotransmitters and neurotransmitter receptors in the nervous system is critical in achieving the complexity of human sensory, behavioral and cognitive function.

Chemical Synapses

• Two main types in the CNS and PNS:
  • Excitatory synapses: evoke depolarizations of the postsynaptic membrane called Excitatory Postsynaptic Potentials (EPSPs).
  • Inhibitory synapses: evoke hyperpolarizations of the postsynaptic membrane called Inhibitory Postsynaptic Potentials (IPSPs).

Excitatory Synapses

• Main neurotransmitters involved in the production of EPSPs are glutamic acid (glutamate) and acetylcholine (ACh).
• Ionic mechanism of EPSPs: opening of channels selective for Na^+, K^+, and sometimes Ca^{2+}.
• This shifts the membrane potential (V) from the resting membrane potential (RMP, usually -65 mV) towards the threshold for the generation of an action potential (AP, about -55 mV).

Inhibitory Synapses

• The neurotransmitters involved in IPSPs are mainly gamma-aminobutyric acid (GABA) or glycine.
• The ionic mechanism of IPSPs is often through the opening of K^+ channels.
• This hyperpolarizes the cell membrane (moves the RMP away from the threshold).
• Inhibitory synapses work independently of excitatory synapses (so IPSPs do not have to be evoked before or after the occurrence of EPSPs).

Mechanisms Used to Gate Ion Channels by Neurotransmitters

• Direct gating: transmitter binds to the receptor/ion channel complex, causing the pore to open and ions to pass through, depolarizing or hyperpolarizing the cell membrane.
  • Effects are very fast in onset (<1 msec) and short-lasting (msec range).
• Indirect gating: transmitter binds to receptors (such as G-protein-coupled, also known as metabotropic receptors), activating a biochemical pathway which involves a G-protein.
  • G-proteins are membrane-enclosed proteins which bind GTP when activated by membrane receptor.
  • This leads to the production of second messengers, such as cAMP.
  • Protein kinases activated by the second messenger phosphorylate specific ion channels, causing them to open or close, and thus, the membrane potential changes.
  • These effects are slower in onset and longer-lasting (seconds to minutes).

Classification of Neurotransmitters

• Many different transmitters are produced by neurons within the brain, each with different physiological effects.
• These effects vary in strength (weak or strong), sign (inhibitory or excitatory) as well as time-course of action (rapid vs. slow onset; rapid vs. slow decay).

Small molecule neurotransmitters ('Classical' neurotransmitters)

• Usually fast, and often acting directly on postsynaptic receptors.
  • Amino acids (glutamate, GABA, glycine)
  • Acetylcholine (ACh)
  • Biogenic amines:
    • dopamine (DA)
    • norepinephrine (NE)
    • serotonin (5-HT; 5-hydroxytryptamine)

Neuropeptides (Neuromodulators)

• Large molecule chemical messengers with indirect (metabotropic) action, or modulatory action on the effects of other neurotransmitters.
• They tend to exert slow and usually a more diffuse action.
• Several dozens of neuropeptides have been identified which may be involved in communication between neurons, e.g., Enkephalin, Substance P, Neuropeptide Y (NPY).

Neurotransmitter Inactivation (and Recovery) after Release

• Removal of neurotransmitter(s) is critical to allow a new signal to follow rapidly.
• The three main mechanisms of removal are:
  • Diffusion: All neurotransmitters are removed from the synaptic cleft to some degree by diffusion.
  • Enzymatic degradation: For example, acetylcholine is rapidly (<1ms) removed from the synapse by acetylcholinesterase; monoamine oxidase (MAO) degrades some biogenic amines; peptidases cleave neuropeptides.
  • Re-uptake (and re-cycling): The most common mechanism used for inactivation of neurotransmitter (e.g., one form of glutamate transporter removes glutamate to presynaptic terminals and astrocytes, and another form of the transporter moves glutamate to synaptic vesicles for storage).

Multiple Receptor Subtypes

• As a further layer of complexity, it is now apparent that not only are there many different neurotransmitters within the brain, but also many transmitters bind to more than one type of receptor.
• The response varies depending on the type of receptor to which the transmitter binds.
• This property increases information handling capacity of neurons.

Glutamate (L-glutamic acid)

• Main Excitatory Neurotransmitter in the CNS
• Due to its importance in brain function (in both physiological and pathological processes), the glutamate receptor and the glutamate transporter physiology remain one the 'hottest' areas in neuroscience research.
• Glutamate binds to four main types of receptors: three are directly gated ion channels (AMPA, NMDA, and Kainate), and one is second messenger-mediated (metabotropic glutamate receptor).
• Although glutamate is the ligand for each of these receptors, the response elicited depends on the type of activated receptor.
• Too much glutamate release (or insufficient re-uptake) leads to excessive activation of neurons through the NMDA and AMPA/Kainate receptors.
• Large Ca^{2+} influx associated with over activation of NMDA receptors causes neuron damage, the process known as excitotoxicity.
• Excitotoxic damage of neurons has been documented in a number of neurological disorders including stroke, epilepsy and traumatic brain injury.

Recap of Lecture 28

• Passive spread of current:
  • Movement of the changes to adjacent atoms.
  • Dissipates.
• Action potential transmission:
  • Two stages: passive current -> full-size AP -> long distances
• Myelination:
  • CNS -> oligodendrocytes
  • PNS -> Schwann cells
  • Forms a good layer of this.
  • Need nodes of Ranvier (allows to open voltage-gated sodium channels and go out open).
• Conduct faster.
• Passive current loss is less.
• Energy requirement is less.
• Discreter.
• Stimulus strength via:
  • Stimulus amplitude.
  • Stimulus frequency.
• Graded.
• All or nothing.