central synapses

• Features of transmission at the NMJ

  • Each muscle fiber receives only one synaptic input
  • Each action potential leads to calcium influx into the presynaptic terminal and the release of 100s of vesicles
  • The end plate potential recruits voltage-gated Na+ channels buried in synaptic folds and reliably triggers a muscle action potential
  • Transmission is terminated by the breakdown of acetylcholine
• Diversity of neuronal subtypes in the CNS

  • Neuronal subtypes differ in their morphology, intrinsic firing properties and mechanisms of communication
  • The patch-clamp technique enables visually-guided recordings from specific neuronal subtypes
  • Synaptic transmission can be studied by electrically stimulating afferent axons and recording the post synaptic response
  • Simultaneous recordings from the 2 connected neurons (paired recordings) enables precise control of action potential firing in the presynaptic neuron and the recording of a unitary postsynaptic response
• Electrical synapses

  • Electrical coupling is not possible at the NMJ due to the issue of impedance matching
  • Electrical coupling can be effective between neurons of a similar size (and thus impedance)
  • Electrical synapses are formed by two hemichannels (connexons made of 6 connexins) that connect across the intercellular space and mostly occur between dendrites of neurons of the same subtype
  • The signal that propagates through the electrical synapses is attenuated (amplitude of frequency reduced) and low-pass filtered (only passing signals below cut-off frequency)
  • Electrical synapses enable graded and bi-directional communication which could be useful for synchronization of local clusters of neurons
  • The precise function of electrical synapses in the CNS remains controversial and these cannot be used for long distance communication
• Chemical Synapses


  • There is a large variety of chemical transmitters used in the CNS and neurons often release more than one substance
  • Around half of the synapses use the excitatory amino acid glutamate whilst around a quarter of the synapses in the CNS use the inhibitory amino acid gamma-aminobutyric (GABA)
  • Excitatory glutamatergic synapses are synonymous with Gray's Type 1 synapses
  • Inhibitory GABAergic synapses are synonymous with Gray's Type 2 synapses

  
• Fast glutamatergic transmission


  1. Glutamate is synthesized from glutamine by glutaminase and concentrated in vesicles via vesicle glutamate transporters (vGluTs)

  2. Glutamate release can activate a range of ligand-gated ion channels (iGluR, AMPA, kainite and NMDA receptors) and G-protein coupled receptors (metabotropic glutamate receptors, mGluR)

  3. Synaptic transmission is terminated by the diffusion of glutamate out of the synaptic cleft and glutamate is subsequently removed from the extracellular fluid via excitatory amino acid transporters (EAATs)

  4. iGluR are permeable to cations and thus a synaptic glutamate release evokes an excitatory postsynaptic potential (EPSP)

  5. The response by an individual synaptic input can be weak (<0.5mV)

  6. Individual responses can show a great deal of variability and failries

  7. Many central neurons receive thousands of convergent weak synaptic inputs – it is the integration of these inputs that determines postsynaptic spiking

  8. Release at a given synapse changes over time in a way that reflects the immediate history of presynaptic activity – it shows short-term plasticity

  9. The connection between a cortical glutamatergic pyramidal neuron and a GABAergic bitufted cell shows short-term facilitation

  10. The connection between a cortical glutamatergic pyramidal neuron and a GABAergic multipolar cell shows short-term depression

  11. Facilitations is thought to be due to residual Ca2+ in the presynaptic terminal which increases the probability of vesicle release following a successive action potential

  12. Depression is though to be due to the refractory state of the release site following vesicle fusion, and continues until a new vesicle can be primed for release

  13. Synaptic short-term dynamics vary across synapses even for the same axon targeting different post-synaptic neurons

  14. Short-term plasticity is a feature of all synapses but is not as obvious at the NMJ as the basal EPP exceeds action potential threshold by a safety margin

  
• Fast GABAergic transmission


  1. GABA is synthesized from glutamate by glutamate decarboxylase (GAD) and concentrated in vesicles via vesicle GABA transporters (vGATSs)

  2. GABA release can activate a range of ligand-gated ion channels (GABAa receptors blocked by picrotoxin and bicuculline) and G-protein coupled receptors (GABAb receptors where the agonist is baclofen and the antagonist is phaclofen and saclofen)

  3. Synaptic transmission is terminated by the diffusion of GABA out of the synaptic cleft and GABA is subsequently removed from the extracellular fluid via GABA transporters (GATs) and recycled

  4. Fast synaptic GABAergic inhibition depends on the activation of GABAa receptors which are pentameric assemblies GABAa receptor subunits

  5. The majority of synaptic GABAa receptors are sensitive to benzodiazepines e.g. diazepam

  
• Main transmitter systems used for long range and diffuse modulation of brain state

  • Acetylcholine
  • Serotonin
  • Dopamine
  • Noradrenaline
• Acetylcholine


  • Cortical-projecting cholinergic are found in the vasal forebrain, brain stem cholinergic neurons are located in the dorsolateral pontine tegmental area
• Serotonin


  • Serotonergic neurons are located in the raphe nuclei
• Major dopamine pathways


  • Nigrostriatal pathway from substantia nigra to dorsal striatum in basal ganglia
  • Mesolimbic pathway from ventral tegmental to ventral striatum, hippocampus and amygdala
  • Mesocortical pathway from ventral tegmental to frontal cortex
  • Tuberofindibular pathway from arcuate nucleus in hypothalamus to pituitary gland
• Noradrenaline


  • The major source of noradrenaline in the brain is from neurons located in the locus coeruleus
• Metabotropic receptors


  Activate intercellular transduction pathways via G-protein coupled receptors
• Inotropic receptors


  Directly form an ion pore (ligand-gated ion channels)
• 1. protein coupled receptors


  • Have 7 transmembrane domains and often appear as dimers, coupled to GTP-binding heterotrimeric G proteins that consist of G alpha, G beta and G gamma subunits
• Types of G proteins

  • Gas (activates plasma membrane adenylyl cyclase increasing cAMP)
  • Gai (inhibits most adenylyl cyclase allowing cellular cAMP to fall)
  • Gaq (activates phospholipase C beta, generating IP3 and diacylglycerol)
• Neuromodulation via volume / paracrine transmission

  • Only 5-40% of monoaminergic and cholinergic axon varicosities form synapses, GPCR are not clustered around release sites
  • Axonal release affects a large volume of tissue, neurotransmitter concentration experienced in receptors is in the order of a few micromolar
  • GPCR have sufficient sensitivity to be activated by low neurotransmitter concentrations and can amplify the signal via intracellular signaling cascades
  • GPCR can have divergent targets including ion channels and gene expression
  • Response depends on pattern of GPCR expression
  • Relatively slow but sufficient to mediate behaviorally-relevant changes in arousal/mood
• For fast synaptic transmission, the identity of the neurotransmitter does not seem that important as the message is conveyed via the activation of a specific set of synapses
• For neuromodulation via paracrine transmission, different signals have to be conveyed by the chemical identity of the neurotransmitter
• Neuromodulation via spillover of fast transmitters


  • Synaptic release of glutamate and GABA leads to spillover into extracellular space which can activate their metabotropic receptors, allowing modulation of neuronal processing depending on current levels of activity in the circuit
• Targets of neuromodulation


  • Presynaptic release
  • Postsynaptic response
  • Neuronal excitability
• Presynaptic neuromodulation


  • Presynaptic GPCRs can modulate ion channels and thus terminal excitability and action-potential induced Ca2+ influx, tending to decrease evoked release
• Postsynaptic neuromodulation


  • Postsynaptic GPCRs can modulate ligand-gated ion channels and thus alter the response to vesicular release
• Neuromodulation of neuronal excitability

  • GPCRs on soma/dendrites can regulate membrane polarization, synaptic integration and spiking patterns
• In the isolated lamprey spinal cord, the central pattern generator is quiescent but can be activated by superfusion of glutamate to mimic supraspinal drive, and further application of 5-HT reduces burst frequency and prolongs intersegmental lags
• The majority of central synapses show activity-dependent changes in synaptic strength, with some synapses adapting/learning very quickly while others require chronic changes in activity patterns
• Long-term potentiation (LTP)


  A form of synaptic plasticity that depends on NMDA receptors and operates at many glutamatergic synapses
• NMDA receptor-dependent LTP at Schaffer collateral/commissural fiber input to CA1 hippocampus

  1. Extracellular stimulation of fibers leads to glutamate release and AMPA/kainate receptor activation, evoking postsynaptic EPSPs

  2. Tetanic stimulation (100 pulses at 100Hz) leads to immediate post-tetanic potentiation and a persistent increase in evoked response (LTP)

  3. LTP is activity-dependent and synapse-specific
• NMDA receptor properties enabling LTP induction

  • Voltage-dependent Mg2+ block, Ca2+ permeability - coincidence of glutamate release and postsynaptic depolarization leads to NMDAR-mediated Ca2+ influx, providing intracellular signal for plasticity
• Expression of LTP


  Postsynaptic mechanisms: Ca2+ influx through NMDAR activates CaMKII, which phosphorylates AMPA channels to increase their conductance and favours insertion/retention of AMPA receptors in the membrane