• Voltage ( ie , potential ) generated due to the distribution ( separation ) of negative and positive charges lining the inner and outer membrane of cells.
• Measured value based on inner membrane charges relative to outer membrane charges.
• Measured in millivolts ( mV )
• All cells have a $V_m$$V_m$

Resting Membrane Potential

• Resting Membrane Potential = $V_m$$V_m$ of a cell when it is not being stimulated or inhibited
• Influenced mainly by the distribution of potassium
• Small influence by the distribution of other ions ( $N{a}^{+}$$Na^+$ and $C{l}^{-}$$Cl^-$ )
• Small influence by proteins ( which have negative charge ) lining inner membrane

• Only the charges stuck to the membrane on either side generate membrane potential
• Membrane = Capacitor

Potassium ( K⁺ )

• $[K{]}_i=\frac{\text{135}mEq}{1L}$$[K]_i = \frac{\text{\color{#FBD037}{135}}\ mEq}{1\ L}$
• $[K{]}_o=\frac{\text{5}mEq}{1L}$$[K]_o = \frac{\text{\color{#FBD037}{5}}\ mEq}{1\ L}$
• $P_k=1.0$$P_k = 1.0$

Sodium ( Na⁺ )

• $[Na{]}_i=\frac{\text{15}mEq}{1L}$$[Na]_i = \frac{\text{\color{#EE4266}{15}}\ mEq}{1\ L}$
• $[Na{]}_o=\frac{\text{140}mEq}{1L}$$[Na]_o = \frac{\text{\color{#EE4266}{140}}\ mEq}{1\ L}$
• $P_{Na}=0.05$$P_{Na} = 0.05$

Chloride ( Cl^- )

• $[Cl{]}_i=\frac{\text{10}mEq}{1L}$$[Cl]_i = \frac{\text{\color{#58CCFF}{10}}\ mEq}{1\ L}$
• $[Cl{]}_o=\frac{\text{100}mEq}{1L}$$[Cl]_o = \frac{\text{\color{#58CCFF}{100}}\ mEq}{1\ L}$
• $P_{Cl}=0.45$$P_{Cl} = 0.45$

NOTE

• Interstitial Fluid Ion Concentrations are the same as in the plasma , lymph , and trans-cellular compartments

• Because potassium has the largest permeability , it has the largest influence on $V_m$$V_m$

• Facilitated Diffusion = ion ( leak ) channels

  • ions moving down the gradient

Maintaining Concentration Gradient

• Sodium Potassium Pump

  • 321 NOKIA

    • 3 Na Out of the cell
    • 2 K Into the cell
    • 1 ATP Used

  • Maintains concentration gradients

  • NOT Responsible for Resting $V_m$$V_m$

• $C{l}^{-}$$Cl^-$ Concentration Gradient is also maintained

• The concentration gradients and permeabilities create an environment that dictates the relative transport of ions

  • Ultimately establishes $V_m$$V_m$

• Therefore , $V_m$$V_m$ is dictated by two separate factors :

  1. Magnitude of the concentration gradients of ions
  2. Permeabilities of the membrane to ions

Passive Transport of Ions

• K⁺ is transported out of the cell during resting conditions

  • At resting $V_m$$V_m$ , permeability of $K^{+}$$K^+$ is the largest

    • Very large amount of positive charge on outer membrane

      • Therefore , $K^{+}$$K^+$ has the greatest influence on resting $V_m$$V_m$

• Na⁺ is transported into the cell during resting conditions

  • At resting $V_m$$V_m$ , permeability of $N{a}^{+}$$Na^+$ is small

    • Small amount of positive charge on inner membrane

• Cl^- is transported into the cell during resting conditions

  • At resting $V_m$$V_m$ , permeability of $C{l}^{-}$$Cl^-$ is large

    • Large amount of negative charge on inner membrane

• Change the transport of ions somehow

  • How ?

    • Change the concentration gradient of ions
    • Change the permeability of ions

• Depolarize = $V_m$$V_m$ becomes more positive

  • Inner membrane becomes either more positive or less negative
  • Outer membrane become either less positive or more negative

• Hyperpolarize = $V_m$$V_m$ becomes more negative

  • Inner membrane becomes either more negative or less positive
  • Outer membrane becomes either more positive or less negative

• Repolarize = $V_m$$V_m$ returns towards resting $V_m$$V_m$ after a change in $V_m$$V_m$

Changing Ion Concentration Gradients

Potassium ( K⁺ )

• Increase extracellular K⁺

  • Decreases the gradient for $K^{+}$$K^+$ transport out of the cell

    • Less $K^{+}$$K^+$ out of cell

      • More positive charge on inner membrane

        • Causes a depolarization

• Decrease extracellular K⁺

  • Increases the gradient for $K^{+}$$K^+$ transport out of the cell

    • More $K^{+}$$K^+$ out of cell

      • Less positive charge on inner membrane

        • Causes a hyperpolarization

• Increase intracellular K⁺

  • Increases the gradient for $K^{+}$$K^+$ transport out of the cell

    • More $K^{+}$$K^+$ out of cell

      • Less positive charge on inner membrane

        • Causes a hyperpolarization

• Decrease intracellular K⁺

  • Decreases the gradient for $K^{+}$$K^+$ transport out of the cell

    • Less $K^{+}$$K^+$ out of cell

      • More positive charge on inner membrane

        • Causes a depolarization

Sodium ( Na⁺ )

• Increase extracellular Na⁺

  • Increases the gradient for $N{a}^{+}$$Na^+$ transport into the cell

    • More $N{a}^{+}$$Na^+$ into the cell

      • More positive charge on inner membrane

        • Causes a depolarization

• Decrease extracellular Na⁺

  • Decreases the gradient for $N{a}^{+}$$Na^+$ transport into the cell

    • Less $N{a}^{+}$$Na^+$ inside the cell

      • Less positive charge on inner membrane

        • Causes a hyperpolarization

• Increase intracellular Na⁺

  • Decreases the gradient for $N{a}^{+}$$Na^+$ transport into the cell

    • Less $N{a}^{+}$$Na^+$ into the cell

      • Less positive charge on inner membrane

        • Causes a hyperpolarization

• Decrease intracellular Na⁺

  • Increases the gradient for $N{a}^{+}$$Na^+$ transport into the cell

    • More $N{a}^{+}$$Na^+$ into the cell

      • More positive charge on inner membrane

        • Causes a depolarization

Chloride ( Cl^- )

• Increase extracellular Cl^-

  • Increases the gradient for $C{l}^{-}$$Cl^-$ transport into the cell

    • More $C{l}^{-}$$Cl^-$ into the cell

      • More negative charge on inner membrane

        • Causes a hyperpolarization

• Decrease extracellular Cl^-

  • Decreases the gradient for $C{l}^{-}$$Cl^-$ transport into the cell

    • Less $C{l}^{-}$$Cl^-$ inside the cell

      • Less negative charge on inner membrane

        • Causes a depolarization

• Increase intracellular Cl^-

  • Decreases the gradient for $C{l}^{-}$$Cl^-$ transport into the cell

    • Less $C{l}^{-}$$Cl^-$ into the cell

      • Less negative charge on inner membrane

        • Causes a depolarization

• Decrease intracellular Cl^-

  • Increases the gradient for $C{l}^{-}$$Cl^-$ transport into the cell

    • More $C{l}^{-}$$Cl^-$ into the cell

      • More negative charge on inner membrane

        • Causes a hyperpolarization

Changing Ion Permeabilities

Potassium ( K⁺ )

• Increase the permeability of K⁺

  • Increases the transport of $K^{+}$$K^+$ out of the cell

    • Less positive charge on inner membrane

      • Causes a hyperpolarization

• Decrease the permeability of K⁺

  • Decreases the transport of $K^{+}$$K^+$ out of the cell

    • More positive charge on inner membrane

      • Causes a depolarization

Sodium ( Na⁺ )

• Increase the permeability of Na⁺

  • Increases the transport of $N{a}^{+}$$Na^+$ into the cell

    • More positive charge on inner membrane

      • Causes a depolarization

• Decrease the permeability of Na⁺

  • Decreases the transport of $N{a}^{+}$$Na^+$ into the cell

    • Less positive charge on inner membrane

      • Causes a hyperpolarization

Chloride ( Cl^- )

• Increase the permeability of Cl^-

  • Increases the transport of $C{l}^{-}$$Cl^-$ into the cell

    • More negative charge on inner membrane

      • Causes a hyperpolarization

• Decrease the permeability of Cl^-

  • Decreases the transport of $C{l}^{-}$$Cl^-$ into the cell

    • Less negative charge on inner membrane

      • Causes a depolarization

• Local , very large and very rapid depolarization followed by repolarization
• Only a handful of cells generate action potentials ( eg , neurons and muscle cells , some glial cells )

• Threshold = depolarized $V_m$$V_m$ that must be reached to generate an action potential
• All-or-None Response = ONLY IF threshold is met will an action potential be generated

Dynamics

1. Neuron is stimulated to cause the $V_m$$V_m$ to depolarize

2. Threshold is reached

3. Voltage-gated $N{a}^{+}$$Na^+$ channels activate rapidly ( $N{a}^{+}$$Na^+$ permeability increases )

   4. Rapid transport of $N{a}^{+}$$Na^+$ into the cell
   5. Causes a very large and very fast depolarization of $V_m$$V_m$ ( < 10 ms )
   6. Action potential passes through zero and towards $E_{Na}$$E_{Na}$
   7. Large depolarizations causes voltage-gated $N{a}^{+}$$Na^+$ channels to inactivate
   8. $N{a}^{+}$$Na^+$ transport into cell stops ( thus , $E_{Na}$$E_{Na}$ is never reached )

3. Voltage-gated $K^{+}$$K^+$ channels open but less rapidly ( $K^{+}$$K^+$ permeability increases )

   4. Rapid transport of $K^{+}$$K^+$ ( but not as rapid as $N{a}^{+}$$Na^+$ ) out of the cell

   5. Causes a very large and very fast repolarization towards resting $V_m$$V_m$ starting at the peak of the action potential

   6. $V_m$$V_m$ continues towards $E_K$$E_{K}$ ( voltage-gated $K^{+}$$K^+$ channels close slowly )

   7. Produces an after-hyperpolarization of $V_m$$V_m$

      • $V_m$$V_m$ is actually more negative ( hyperpolarized ) than resting $V_m$$V_m$

4. Resting $V_m$$V_m$ re-established by channels responsible for establishing resting $V_m$$V_m$

Frequency

• Maximum frequency is dictated by the refractory period

  • Shorter refractory period = greater number of action potentials

• Directly proportional to the stimulus strength

  • Frequency $\propto$$\propto$ Stimulus Strength
  • The greater the stimulus , the greater the action potential frequency

• Sub-Threshold Stimulus

  • Very small stimulus that does not cause a cell to reach threshold

    • No action potential generated

• Threshold Stimulus

  • Stimulus that causes a cell to just reach threshold

    • One action potential generated

• Submaximal Stimulus

  • Greather than threshold stimulus but less than maximal stimulus

    • Greater than one action potential but less than the number of action potentials generated with a maximal stimulus

• Supra-Maximal Stimulus ( greater than maximal stimulus )

  • Action potential frequency does not increase despite larger stimulus

    • Cannot go beyond a maximum action potential frequency
    • Stimulus is greater than maximum stimulus , but still same frequency of action potentials

Conduction

Propagation / Spread of Action Potentials Along a Membrane

• Action potential does NOT move across a membrane

• Action potential causes the generation of another in an adjacent region

  • Analogous to dominos toppling , one after another

• Velocity of conduction in axons depends on axon diameter and myelin

  • Larger axons conduct action potentials faster

    • Greater surface area with more voltage-gated ion channels

  • Myelinated axons conduct action potentials faster

    • More myelin = faster conduction

Continuous Conduction

• Occurs in unmyelinated axons and membranes of excitable cells

• Action potential in one region stimulates another in an adjacent region

• Conduction velocity is less than 2 meters / second

• Dynamics

  1. Sodium ions from action potential diffuses to adjacent region

  2. Causes depolarization of the membrane

  3. When threshold is reached , another action potential is generated

  4. Conduction of action potentials continues in one direction

     • ensured by the refractory period

Saltatory Conduction

• Occurs solely in myelinated axons

  • No voltage gated channels on myelin

• Action potentials generated at the nodes of Ranvier

  • High concentration of voltage-gated $N{a}^{+}$$Na^+$ and $K^{+}$$K^+$ channels at nodes

• Conduction velocity is anywhere from 3 to 120 meters / second

• Dynamics

  1. Sodium ions from action potential diffuses to adjacent node

  2. Causes depolarization of membrane

     • myelin sheath allows diffusion of sodium to be rapid.

  3. When threshold is reached , another action potential is generated

  4. Conduction of action potential continues in one direction

     • ensured by the refractory period

• Junction between two cells that allows communication between those two cells
• Two types of synapses

Electrical Synapse

• Communication between two cells via gap junctions ( channels )

• Molecules flow freely through gap junctions when open

• Allows for :

  • rapid passage of information between adjoining cells
  • coordination between electrically coupled cells

Chemical Synapse

• Communication between two cells via release of neurotransmitters

• Presynaptic Membrane = membrane at the synapse that is carrying the information

• Postsynaptic Membrane = membrane at the synapse that is receiving the information

• Synaptic Cleft = small space between presynaptic and postsynaptic membranes

• Neurotransmitters = chemicals released from presynaptic cell to postsynaptic cell

  • Produced by presynaptic cell and most are stored in synaptic vesicles

  • Gaseous neurotransmitters produced and released when needed

    • Therefore , gaseous neurotransmitters are NOT stored.

Synaptic Transmission

1. Action potential conducts to synaptic terminal of presynaptic membrane

2. Causes voltage-gated calcium channels to open

3. Intracellular calcium concentration increases ( via calcium channels )

4. High calcium causes synaptic vesicles to fuse with presynaptic membrane

   5. Neurotransmitter is released into synaptic cleft via exocytosis
   6. Diffuses across synaptic cleft
   7. Binds to specific receptors of the postsynaptic membrane

4. High calcium causes production of gaseous neurotransmitter

   5. Neurotransmitter released from presynaptic cell via diffusion
   6. Diffuses across synaptic cleft and into postsynaptic cell
   7. Modulates ion channels in the postsynaptic membrane

Fate of Neurotransmitters

• Reuptake of chemical neurotransmitter by presynaptic membrane

• Gaseous neurotransmitters are metabolized by postsynaptic cell

• Reuptake inhibitor = drug that inhibits the reuptake of neurotransmitters

  • antagonist to the transport process

  • neurotransmitter remains in the synaptic cleft longer

    • Effect of the neurotransmitter is enhanced

  • Administered when natural neurotransmitter level is low

Post Synapatic Potential

• Transient $V_m$$V_m$ change of postsynaptic membrane

  • Due to neurotransmitter release on postsynaptic membrane

• Excitatory Postsynaptic Potential ( EPSP ) = depolarization followed by repolarization

  • Influx of cations ( eg , $N{a}^{+}$$Na^+$ ) or efflux of anions ( eg , $C{l}^{-}$$Cl^-$ )

• Inhibitory Postsynaptic Potential ( IPSP ) = hyperpolarization followed by repolarization

  • Infflux of anions ( eg , $C{l}^{-}$$Cl^-$ ) or efflux of cations ( eg , $K^{+}$$K^+$ )

Post Synaptic Plasticity

• Ability of some structure of a synapse to change

  • eg , decrease or increase in neurotransmitter release
  • eg , decrease or increase in the number of receptors

• Formation of new synapses or loss of synapses

  • More or less presynaptic terminals

• Large "event" must take place to cause plasticity

Acetylcholine ( ACh )

• Found in the CNS and PNS

• Excitatory or inhibitory ( depends on the cell type )

  • In skeletal muscle : ACh = excitatory = $N{a}^{+}$$Na^+$ enters
  • In cardiac muscle : ACh = inhibitory = $K^{+}$$K^+$ leaves

• Important in arousal , sleep , attention , memory

• Used in the somatic and autonomic nervous system

• Loss of ACh-producing neurons implicated in memory loss with Alzheimer's

  • Treatment option is ACh reuptake inhibitor

• 1st ever discovered

Monoamines

Serotonin ( 5 -HT )

• Found in the CNS and PNS ( most found in the gut ( 90% ) )

• Excitatory or inhibitory ( depends on the cell type )

• Important in temperature regulation , sleep , mood , nausea , vomiting

  • nausea is likely from high levels of 5-HT

    • give 5-HT antagonist

• Stimulates the gut ( gut-brain axis )

• Low levels in the brain linked to :

  • Depression , Anxiety , Obsessive compulsive disorder , PTSD

  • Treat with selective serotonin reuptake inhibitors ( SSRIs )

    • eg , Prozac , Paxil , Zoloft , Celexa , Lexapro

  • Treat with Psychotherapy :

    • Talk therapy
    • Cognitive behavioral therapy
    • Exposure therapy

• MDMA / Ecstasy / E / X / Molly / etc

  • Serotonin reuptake inhibitors

Norepinephrine

• Found in the CNS and PNS

• Excitatory or inhibitory

• Important in decision making , attention and mood

• Neurotransmitter of the sympathetic nervous system

• Low levels in the brain linked to :

  • Depression , attention deficit disorder

  • Treat with norepinephrine reuptake inhbitor

    • eg , Wellbutrin , Ritalin

  • Treat with psychotherapy

Dopamine

• Primarily found in the CNS

• Excitatory or inhibitory

• Important in movement , attention , motivation , and pleasure

  • different brain regions responsible for each sub-type

• High levels in the brain linked to Tourette's and psychosis

  • Treat with dopamine receptor antagonist

• Low levels in the brain linked to :

  • Depression , Attention deficit disorder , Addictive behavior

  • Treat with dopamine reuptake inhibitors

    • eg , Wellbutrin , Ritalin , Chantix ( addictive )

  • Treat with psychotherapy

• Loss of dopamine-producing neurons causes Parkinson's disease

  • substantia nigra , smooth muscle control

Amino Acids

Glutamate

• Found primarily in the CNS

• Major excitatory neurotransmitter in the CNS

  • EPSPs , depolarization , Action Potentials

• Has many functions including learning and memory

• High levels in the brain cause seizures and neural degeneration

  • Treat with drugs that block glutamate release and receptors

GABA

• Found primarily in the CNS

• Major inhibitory neurotransmitter in the CNS

• Drugs that increase GABA used to treat epileptic activity

  • GABAergic drugs

    • "ergic" = mimic

  • Over exciting neurons can cause neurons to die = neuron degeneration

  • ALS = motor neuron death

Glycine

• Found primarily in the CNS
• Inhibitory neurotransmitter

Neuropeptides

Endorphines and Enkephalins

• Found in the CNS and PNS

• Opioid compounds

• Inhibitory

• Important in regulation of pain and gut motility

  • Diminishes pain and slows the gut

• Morphine , Oxycontin , Heroin = agonists to opioid receptors

• Narcan = antagonist to opioid receptors

  • Therefore , narcan blocks the effect of heroin

Substance P

• Found in the CNS and PNS
• Excitatory
• Important in the regulation of pain , anxiety , nausea , and breathing
• Inhibiting Substance P receptors reduces pain and prevents nausea

• Cannot be stored
• Produced as they are needed

Nitric Oxide

• Found int he CNS and PNS

• Excitatory or Inhibitory

• Involved in many processes

  • eg , erection , blood vessel tone , memory

Carbon Monoxide

• Found in the CNS and PNS
• Excitatory or inhibitory
• Thought to be a co-neurotransmitter with nitric oxide
• Similar functions to nitric oxide

Locations = Hippocampus , Prefrontal Cortex , Amygdala , Striatum , Mammillary Bodies

Sensory Memory

• Very short-term retention of sensory input from the external environment

• Sensory information form the external environment that is scanned and evaluated

  • One does not realize this is happening

• Lasts less than one second

• Electrical in nature

  • Solely a change in $V_m$$V_m$

• Gone if it is ignored

• If perceived ( not a conscious act ) it is stored in short-term memory

Short-Term Memory

• Lasts seconds to approximately one minute

• Electrical in nature

  • Solely a change in $V_m$$V_m$

• Forgotten if an effort is NOT made to retain it or an "impression" is NOT made

Long-Term Memory

• Lasts minutes to hours and as long as a lifetime

• Information stored when an effort is made or an impression is made

• Synapatic in nature

• Synaptic plasticity :

  • eg , increased neurotransmitter release
  • eg , increased receptor sensitivity
  • eg , increased number of receptors
  • eg , new synapses form

• Two types :

  1. Declarative / Explicit

     • Retention of events , people , places , facts , etc

  2. Procedural / Implicit

     • Development of Skills

       • eg , walking , eating with a spoon , driving a car

     • Conditioned Reflexes

       • eg , associating an event / person with a smell