Neurotransmitters 

Axon & Synapse Function

Resting Membrane Potential: Value of potential across the membrane when a neuron is not transmitting information

  • Steady-state condition with no NET FLOW of ions across the membrane…no change in the distribution of ions across the membrane, although individual ions may move across through leaky channels
  • A neuron at rest = a capacitor, separation of the electrical charges on either side of the plasma membrane
  • unequal distribution of ions is necessary for the neuron to be excitable

Electrical Potential: difference in electrical charge carried by ions

  • Rapid change in electrical charge across the membrane → transmits info/signal along the axon → release of chemical transmitters

Flow of Information in a Neuron

  1. Signals (neurotransmitters) enter through the dendrite and converges on the axon hillock
  2. Signals are summated and converted to an action potential (AP)
  3. An “All-or-Nothing” action potential is sent down the axon
  4. Communication between the pre-synaptic & post-synaptic cells

Propagation of Information by Neurons

Four types of membrane channels allow ions to flow across the membrane

  • Leaky channels
  • Modality-gated channels: activated bye physical change…ex: temperature, pressure, etc.
  • Ligand-gated channels: ion/neurotrransmitter molecule binds to a receptor on the surface of a channel
  • Voltage-gated channels: electric current (ion flow) dependent
      * Gated: the channel will open ion response to a stimulus

Synapse Mechanics

Chemical vs Electrical

Chemical: where we see synaptic vesicles holding the neurotransmitters travel through the presynaptic membrane, then released into the synaptic cleft to bind to the receptors on the postsynaptic membrane

Electrical: typically seen as communication through gap junctions, where we see electrical/ion flow dependent channels

Chemical Synapse

3 components: Presynaptic axon, presynaptic terminal, postsynaptic cell

  1. Action potential travels down presynaptic axon to the presynaptic terminal
  2. Once the AP reaches the presynaptic terminal it opens the Ca2+ channel and the influx of Ca2+ pushes the vesicles carrying the neurotransmitters out
  3. The vesicles will “pop” releasing the neurotransmitters into the synaptic cleft where they will flow and bind to its receptors on the postsynaptic cell (the dendrite)
  4. The binding → alters the postsynaptic cell function
  • Direct Activation of ion channels = ONLY ONE RESPONSE per synapse/cell

Excitation vs Inhibition

The neurotransmitters that travel through the synapse can influence the next cell/nerve in one of two ways…

  1. Excitatory
  2. Inhibitory
  • Excitatory: elicits a response
      * vesicles appear to be round clear or have a dense core
      * postsynaptic thickening will occur (asymmetrical)
      * prevalent on distal dendrites
  • Inhibitory: inhibits the response
      * multiform or oval(ish) vesicles
      * Symmetrical pre/post membranes
      * prevalent on the soma, proximal dendrite and axon terminal
  • Postsynaptic membrane, changes in membrane potential are either Excitatory (local depolarization) or Inhibitory (local hyper-polarization)
  • Inhibition by Chloride Hyper-polarization: neurotransmitter stimulates Cl- channel to open, the negative change of CL- hyper-polarizes the neuron, causing the membrane potential to be lower than normal requiring additional stimulation to reach action potential
  • Presynaptic Facilitation & Excitation: more neurotransmitters are released …happens as the presynaptic axon releases that slightly depolarize the axon terminal on the second axon
      * changes the amount and type of neurotransmitter released
      * happens a lot on in the cerebellum
      * modifies the job so that the muscle activity is an appropriate response
  • Presynaptic Facilitation and Inhibition: less neurotransmitter is released…occurs when the axon releases neurotransmitters that hyper-polarize the second axon
  • Types of synapse endings:
      * Terminal passant: precision, found in motor system (1to1)
      * Bouton passant: mass communication, found in the cerebellum & other locations (memory sensors)

Interactions b/w Neurons

  • Divergence & Convergence contribute to the distribution of information throughout he nervous system
      * Convergence: MULTIPLE INPUTS from a variety of cells terminate on a single neuron (loose one there are “backups”)
      * Divergence: a single neuron with many branches that end on many cells (ex: within the cerebellum…recovering from polio is dependent on divergence, maintaining posture…communication to many muscles, loss of one neuron=major effect)

  Why is inhibition more prevalent?
  * Because in order to produce a productive and reasonable outcome there must be a component of inhibition to balance the amount of excitation

Neuromodulation

Neuromodulators: alter neural function by acting away from (not directly on) the synaptic cleft

  • effects have a slow onset but usually last longer (minutes to days long) than the effect of neurotransmitters (happens in seconds)
      * Substance P “pain neurotransmitter released during cell damage”..involved in pain perception, released into extracellular space
      * diffuses into the extracellular fluid → stimulate multiple neurons
  • G-Protein Modulators - receptor indirect ion channel activation
      * modifies the receptor on the postsynaptic cell to change the function and sends a new/modified signal to next cell → can cause multiple responses in one cell
      * Binding to multiple sites can be more efficient in large responses (amplifies the signal)
  • Ligand gated receptor
      * receptor channels → briefly opens ion →causing local depolarization/hyper-polarization of membrane
  • Receptor Regulation: Dendrite mediated
      * Cells regulate activity in several ways
      * In response to frequent stimulation by a ligand, cell will decrease receptor activity by…
        * receptor internalization (to much stimulation the cell will slowly shut down)
        * receptor inactivation (drug tolerance can be due to lack of receptors)
      * Overstimulation of postsynaptic receptors can cause a decrease in the number of receptors at the surface
      * activated receptors are internalized when part of postsynaptic membrane folds into the cell
      * Inactivation leaves the total number of receptors at the membrane constant but switches off (they can come back because the system has plasticity)

Myasthenia Gravis

  • Grave muscle weakness: presents as fluctuating fatigue and weakness
  • problem of the postsynaptic region of the neuromuscular end plate
  • associated with a family history of autoimmune disease
  • likely to see other autoimmune diseases ion these patients
      * high incidence of thymic disease…demonstrates as thymic hyperplasia, 10-15% have thymomas
  • In MG there is a deficiency in the number of acetylcholine receptors at neuromuscular junction → clinically seen as muscle fatigue w/sustained or repeated activity
  • Presenting symptoms
      * Hoarse voice
      * Difficulty chewing or swallowing
      * Fatigue with talking (oropharyngeal muscles)
      * Decreased respiratory function
      * Drooping eyelids
      * Double vision/eye movement fatigue
      * Difficulty walking up stairs
      * Muscles with small motor units are the muscles MOST AFFECTED (ocular muscles and hands)
      * Overall facial weakness (almost always present)
  • Treatment Options
      * Removing thymus/thymectomy: try to induce remission
      * Plasmapheresis, corticosteroids and immunosuppressant drugs: reduce the levels of antibody to ACH receptor
      * Increasing the amount of ACH available at the neuromuscular junction w/cholinesterase inhibitors (cholinesterase is responsible for the breakdown of ACH)

Neurotransmitters

Two types:

  • Fast-acting: they act directly
      * transmission takes 1/1000 of a second
      * directly by activating ion channels
  • Slow-acting: they act indirectly
      * transmission requires 1/10 of a second
      * indirectly by activating proteins inside the postsynaptic neuron

Synaptic Receptors

Typically named for the transmitter/modulator they bind to, produce either direct or indirect actions

  • Act directly: the receptor and ion channel make up a single functional unit
  • Act indirectly: using a cascade of intracellular molecules to activate ion channels or other changes (multiple changes)

Specific Neurotransmitters: formulate different action in the nervous system

AMINES

  • Dopamine (DA): affects motor activity, cognition, & behavior
  • Norepinephrine (NE): plays a vital role in active surveillance by increasing attention to sensory information
  • Serotonin: affects sleep, general arousal, cognition, perception, motor activity and mood
  • Histamine: Concentrated in hypothalamus…autonomic functions

Cholinergic Pathways: Excitatory (+)

  • Arise in the nucleus basalis → projects to Cortex & Fornix Hippocampus
  • Important for learning and memory, involved w/Dementia

Dopaminergic Pathways: Excitatory (+)

  • Arise from 2 sites
      * Substantia Nigra → Corpus Striatum
  • Ventral Tegmental Area (VTA) → septum, amygdala and to cortex (frontal lobe)

Dopamine is important…

  • Too little → Parkinson’s
  • Too much → Schizophrenia

Noradrenergic Pathways: Excitatory/Mixed (+/-)

  • Locus Ceruleus → moves rostrally in the Median Forebrain Bundle & supply broad areas of cortex
  • Noradrenergic projections are thought to be important for learning and “plasticity” of the brain

Serotonergic Pathways: Excitatory/Regulatory (+/-)

  • Arise from Raphe Nuclei → arise in the midbrain, runs in the Median Forebrain Bundle
  • Serotonin plays a role sleep wake cycle and mood regulation
      * Too little → depressed, use of an SSRI (inhibitor, leaves extra serotonin in the brain)

Amino Acids:

  • Glutamate: (primary) fast excitatory transmitter of CN
      * over activity of NMDA receptors may cause epileptic seizures
      * MAIN EXCITATORY transmitter in CNS
      * high levels → seizures
      * Neuron death increases Glutamate Levels in CNS
        * Excitotoxicity = neuron dies, releases Glu→ exciting neighboring neurons, too much excitement → overwhelmed neurons die (and the cycle repeats)
        * “propagating problem” = increased metabolic demand → increased ischemia
        * Seen in Brain injury & Stroke
        * Damage leads to swelling and edema = pressure on all regions of the brain, lack of O2
      * Glycine: inhibits postsynaptic membranes, mainly in the brainstem and spinal cord
  • GABA: slow-acting responses
      * Linked to ion channels as a second messenger system
      * inhibitory in the spinal cord
      * MAIN INHIBITORY TRANSMITTER in CNS → Prevalent effects in the PNS
      * Helps provide smooth controlled movements, w/out it very spastic movements and will “Stay On” all the time

Peptides

  • Opioid Peptides: endorphins, enkephalins & dynorphins…feel good chemicals in our body
      * inhibits neurons in the CNS that involved in pain perception
  • Substance P
      * stimulates nerve endings at the site of injury…(supposed to balance out w/opioid peptides)
      * increases sensation and awareness of pain
      * PNS: released by nerve endings in skin, mm and joints
      * CNS: released by substantial nigra, amygdala, hypothalamus & cerebral cortex
      * increased levels → chronic pain syndromes
      * NOT A SYNAPTIC RELEASE
  • Calcitonin gene-related peptide
  • Endorphins (-)
      * opioid receptors: inhibit pain signaling, runners high & can be activated by stress hormones

Other

  • Nitric Oxide: regulates the vascular system in the periphery and also active in the brain …changes in pain perception
      * does not require a receptor, just diffuses across the membrane
  • involved in persistent changes in the postsynaptic response to repeated stimuli and in cell deaths

Disorders of Synaptic Function: Channelopathy

  • Disease involves dysfunction of ion channels
  • In some cases causes epilepsy & migraines
  • Channelopathies affecting skeletal muscles cause paralysis or slow relaxation following muscle contraction

Clinical Application of Neurotransmitter

  • Norepinephrine: Fat oxidation, sympathetic stimulation (fight or flight)
  • Serotonin: Impulsivity, Moral Decision making, Obsessive-Compulsive
  • Dopamine: Reward-seeking, Motor Control (movement), Hunger
  • Norepinephrine, Serotonin & Dopamine → Emotion, Cognition & Mood
  • Norepinephrine & Serotonin → Anxiety & Irritability
  • Norepinephrine & Dopamine → Motivation & Schizophrenia
  • Dopamine & Serotonin → Aggression & Harm avoidance