Notes

How Do We Assess the Function of Neurons

• By Electrophysiology because neurons generate and transmit electrical signals via ions.
• Neurons are polarized cells (resting membrane potential). The difference in voltage across the cell membrane when a neuron or muscle cells is not producing an AP.
  • A typical value is: -70mV (-50 to -90).
  • A cell that exhibits a membrane potential is said to be polarized.
• Why is the inside of the cell more negative? Because of thefollowing:
  • The resting membrane is 10-100 times more permeable to K+ than to Na+.
  • K+ tends to leak out of the cell down its concentration gradient, carrying positive charge with it, and unable to carry Cl- with it because Cl- has higher concentration outside.
  • The non-diffusible anion (protein, sulphate and phosphate ions) cannot leave the cell.
• The Action Potential is a very fast and transient change in the polarity of the neuronal membrane that breaks the ionic equilibrium.
• Synaptic transmission is the mode of communication between neurons.

Types of Synapses

• There are two types of synapses in the nervous system
  • Chemical Synapses (2 types)
    • Excitatory (Asymmetric)
    • Inhibitory (Symmetric)
    • Chemical Synapses physically connect across the cleft.
  • Electrical Synapses (3 types of channels)
    • Pannexin
    • Innexin
    • Connexin (5 groups)
    • Electrical synapses are gap junctions.
    • Electrical Transmission allows the rapid and synchronous firing of interconnected cells.

Synaptic Transmission (Post-synaptic)

• Two different Neurotransmitter Receptor Types
  • Ionotropic (Ligand-Gated Ion Channels)
    • Short latency: rapid signals approx. 10ms.
    • Localization: usually postsynaptic.
    • Function: mediate fast synaptic transmission.
    • They change their conformation upon binding of the NT.
    • Typically 4/5 transmembrane domains
  • Metabotropic (GCPRs) (G-Protein Coupled Receptors)
    • Long latency: slow signals approx. 10sec.
    • Divergence: amplification of weak signals.
    • Convergence: integration of multiple inputs.
    • Localization: presynaptic and postsynaptic.
    • Function: modulate fast synaptic transmission.
    • Typically 7 transmembrane domains.
    • Three classes of GPCRs:
      • Class A (391 Olfactory)
      • Class B
      • Class C (GABAB)
    • The G-Protein has three subunits (alpha, beta, gamma).
    • It generates a cascade of events: NT arrives to receptors binds to G-protein the G-Protein subunits splits (GTP to GDP) Most of the work is done by the alpha subunit.
    • Divergent Roles for GPCRs: There are 3 main sequences of events:
      • cAMP System
      • Phosphoinositol System
      • Direct G Protein-Gating
    • Benefits of GPCRs
      • Amplification of the signal.
      • Modulation of cell function over a broad temporal range.
      • Diffusion of the signal to a large cellular volume.
      • Cross talk.
      • Coordination of diverse cell functions.

Glutamatergic-Excitatory

• Ionotropic Glutamate Receptors - AMPARs.
• Excitatory synapses depolarize the neuron.
• The generation of an EPSP: an impulse arriving in the presynaptic terminal causes the release of neurotransmitter. The molecules bind to transmitter-gated ion channels in the postsynaptic membrane. If Na+ enters the postsynaptic cell through the open channels, the membrane will become depolarized. The resulting change in the membrane potential (Vm), as recorded by a microelectrode in the cell, is the EPSP.
• Channels are very specific for certain ions, a small change in the gene code can block the passage of certain ions (e.g., Ca2+).
• Receptors are affected by drugs (e.g., PCP blocks NMDA receptors giving hallucinations).
• Protein complexes allow receptors to be presented and work as channels, but such protein complexes can be removed by the cell (plasticity).

GABAergic - Inhibitory

• Ionotropic receptor type topological arrangement - GABAARs.
• The Generation of an IPSP: an impulse arriving in the presynaptic terminal causes the release of neurotransmitter. The molecules bind to transmitter-gated ion channels in the postsynaptic membrane. If Cl- enters the postsynaptic cell through the open channels, the membrane will become hyperpolarized. The resulting change in membrane potential (Vm), as recorded by a microelectrode in the cell, is the IPSP.
• Several drugs to sleep better or relax are based on this concept, indeed these drugs target inhibitory receptors keeping them open for longer which allows more passage of Cl-, which in turn reduces the general spiking activity of the brain, thus inducing a sensation of relax which favors sleeping. Similar drugs are used also to cure Epilepsy.

Post-Synaptic Integration

Effects of Spatial Location on Synaptic Impact Different Types of Chemical Synapses based on Spatial Location

• Axosomatic Synapses
• Axodendritic Synapses
• Axo-axonic Synapses

Electronic Attenuation of Electrical Signals with Distance

Place-Dependent Post-Synaptic Functional Impact Signals are amplified in synapses through channels like NMDA, which is voltage-dependent.

Effects of Timing on Synaptic Impact EPSP Summation (a) A presynaptic action potential triggers a small EPSP in a postsynaptic neuron. (b) Spatial summation of EPSPs: When two or more presynaptic inputs are active at the same time, their individual EPSPs add together. (c) Temporal summation of EPSPs: When the same presynaptic fiber fires action potentials in quick succession, the individual EPSPs add together.

Integrating Synaptic Signals in a Simple Circuit Feed-Forward Inhibition in the Reflex Spinal Cord Circuit In the Spinal Cord reflex we have a circuit that induces opposite effects (excitation and inhibition) with respect to extensor and flexor muscular neurons. Indeed, when the sensory neurons sense a change in muscular stretch are excited and spike. The action potential generated from the sensory neuron, as shown in the image, generates an EPSP in the extensor MN which induces a muscle extension, at the same time the action potential excites an interneuron that inhibits the Flexor MN, thus relaxing the flexor facilitating the muscle extension.