Neurons and Glial Cells

• All cells in the body have identical material
• Embryonic stem cells form two primary types of cells for the nervous system
• Neurons transmit electrical signals throughout the body
• Glial cells insulate, protect, and metabolically support neurons
• Adult stem cells repair damaged tissue (not pluripotent) in the organ they reside
• Adult stem cells have limited therapeutic potential
• Adult stem cells are difficult to isolate and get large quantities for transplantation
• With age, the number of adult stem cells decrease

Glial Cells

• Oligodendrocytes produce myelin sheaths on axons in the central nervous system (CNS)
• Schwann cells produce myelin sheaths on axons in the peripheral nervous system (PNS)
• Astrocytes are large, star-shaped cells providing structural support by intertwining with neurons
• Astrocytes maintain the environment around neurons by taking up neuron chemicals
• Microglia are smaller than astrocytes
• Microglia remove dying cells (neuron damage)
• Microglia are the primary source of immune response in the CNS (i.e., inflammation reaction)

Neurons

• Neurons transmit information in the form of electrical signaling over long distances
• Sensory neurons
• Interneurons
• Motor neurons
• Sensory neurons convert physical stimuli into electrical signals that are sent to CNS via circuits of interneurons
• Sensory neurons transmit sensory information from sensory receptors to the CNS
• Sensory information helps with feeling

Interneurons

• Interneurons are nerve cells in the CNS forming complex neural circuits for sensorimotor integration
  • Interneurons are responsible for decision making, cognition, memory, etc

Motor Neurons

• Motor neurons transmit electrical signals from the CNS to muscles
• Controls voluntary movement

Soma/Cell Body

• The soma/cell body is surrounded by extracellular fluid
• Synthesizes proteins (i.e., enzymes, receptors)
• Contains nucleus
• Contains pairs of chromosomes, which are long strands of DNA (deoxyribonucleic)
• Genes code for the production of a specific protein molecule and is a small portion of the chromosome
• Neurons are filled with cytoplasm

Dendrites

• Dendrites receive signals and pass it to the soma
• Has thousands of receptors on dendrites
• Dendritic spines increase the receiving surface area
• Dendrites and spines are modified in response to changes in synaptic transmission
• The most profound change is the number of spines in brain development
• Long-lasting changes in synaptic activity change the size, number, and shape of spines
• Mushroom-shaped spines are more efficient
• Dendritic atypicalities during brain growth indicate intellectual disability
• In people with schizophrenia, the atypical spines (less spines) are typical size spines with reduced spine density in the prefrontal cortex (PFC) along with intact intelligence, but cognitive and negative symptoms
• Negative symptoms: atypically absent, can't receive emotion and pleasure well
• Positive symptoms: atypical presents, hallucination

Axons

• Axons are filled with axoplasm
• Send action potential (axon hillock) to the axon terminal
• Axons bifurcate into axon collaterals
• Terminal buttons contain synaptic vesicles of neurotransmitters
• Axons are wrapped with myelin sheath
• Nodes of Ranvier increase speed of condution by speeding up action potential down the axon
• The thicker the myelin is, the quicker the action potential down the axon
• Multiple sclerosis (MS) is an autoimmune disease affecting oligodendrocytes causing myelin loss: confined to the brain, spinal cord, and optic nerves

Autoreceptors

• Neuronal receptors are specific for the same neurotransmitter released where neuronal receptors inhibit further release
• Terminal autoreceptors inhibit further transmitter release on the axon terminal
• Terminal autoreceptors are important when firing rapidly
• Somatodendritic autoreceptors slow cell firing causes less neurotransmitter to release
• Less action potential and neurotransmission
• Drugs can stimulate or block specific autoreceptors

Neurotransmission

• Transmit neurotransmitters in synaptic vesicles to the axon terminal
• An action potential must travel the length of the axon to cause synaptic vesicles to release neurotransmitters into the synapse
• Presynaptic neuron transmits to the postsynaptic neuron
• Pre and postsynaptic neurons don't touch each other, but a small gap inbetween is present
• Transmits from one direction, pre to post synaptic
• Convergence receives and integrates information from numerous cells
• Divergence is the integrated information being transmitted to other neurons
• Receptors are specialized to receive only certain types of neurotransmitters

Mechanisms of Neurotransmitter Inactivation

• Neurotransmitters are removed from the synapse through:
• Enzymatic breakdown where enzymes break down neurotransmitters
• Transporters:
  • Reuptake transports out of the synapse by the presynaptic cell
  • The synapse is transported by nearby glial cells, astrocytes

Psychoactive Drugs that Prevent Reuptake

• Some psychoactive drugs block transporters, enhancing neurotransmission
• Cocaine blocks transporters for dopamine (DA), serotonin (5-HT), & norepinephrine (NE)
• Selective Serotonin Reuptake Inhibitors (SSRIs) block 5-HT (serotonin) transporter
• Since 5-HT is reuptake 5-HT remains in the synaptic cleft for a longer time

Cell Membrane

• Made of a phospholipid layer (lipid-soluble where freely pass through)
• Includes proteins
• Receptors are the initial site of action of ligands
• Enzymes
• Transporters remove of neurotransmitters from the synaptic cleft
• Contain Ion channels

Ion channels

• Ion channels are relatively specific for particular ions
• Most channels are opened momentarily by specific stimuli to allow passage of ions through gated channels
• Channels open and briefly closes again
• Ligand-gated channels are regulated by a ligand binding to a receptor site associated with that channel
• Voltage-gated channels are regulated by voltage differences across the membrane

Resting State of Neurons

• Neuron is polarized at its resting state (-70mV) as the resting membrane potential
• The membrane has selective permeability
• Uneven ion distribution inside and outside the cell
• Positively charged ions are outside the cell, and negatively charged ions are inside the cell
• For potassium (K+) ions, concentration gradient and electro-static pressure are important for ion distribution
• K+ moves more freely through the membrane
• Some of K+ channels are not gated in resting potential
• Equilibrium potential for K+ balances the inward electrostatic pressure with the outward concentration gradient of K+
• Sodium (Na+) - K+ pump is an enzyme that helps to maintain the resting potential
• 3 Na+ ions are exchanged for 2 K+ maintaining a "-" charge inside the cell

Threshold for Firing

• Threshold for firing: -50mV membrane potential
• Voltage-gated Na+ channels open generally a rapid change from -70mV to -50mV

Local Potentials

• Localized change in voltage across the membrane following the opening of ligand-gated channels
• Sodium is more concentrated
• SODIUM causes Depolarization: the inside of the cell becomes more “+”, increasing the likelihood of an action potential (is excitatory) (cell would fire an action potential)
• Chloride causes Hyperpolarization: the inside of the cell becomes more “-”, reducing the likelihood of an action potential (is inhibitory) (reduce an action potential would fire)
• Hyperpolarization is negative and depolarization is positive
• Drugs/neurotransmitters cause EPSPs or IPSPs

Local Potentials: Relevance in Psychopharmacology

• Local potentials are generated on the dendrites
• Local potentials show summation (integration) (small things can add up to = larger change)
• Integration of EPSPs/IPSPs occurs in the axon hillock, and if the threshold is reached (-50mV) (resting potential = -70mV)
• When hyperpolarization & depolarization occur simultaneously, they cancel each other out
• Local potentials are graded
• As soon as the stimulus stops, the ion channels close
• EPSPs excitatory postsynaptic potentials and IPSPs are inhibitory postsynaptic potentials

Action Potential

• Upon integration, membrane potential is changed from resting to the threshold for firing
• Concentration gradient & electrostatic pressure, move large numbers of Na+ ions into the cell
• -50mV to +40mV: rising phase of action potential
• Absolute refractory period is the short time after an action potential when Na+ channels close & remain closed
• When resting levels are reached, Na+ channels are ready to open
• During the rising phase, voltage-gated K+ channels open & remain open
• Relative refractory period is a short hyperpolarizing phase after an action potential, where an intense excitatory stimulus is needed for an action potential
• All-or-none: reaching the threshold will generate an action potential, however more EPSPs will not make it larger

Neurotransmitter Receptors

• Transmit a signal from the presynaptic --> postsynaptic cell
• Neurotransmitter physically disengages after binding to the receptor & activating it
• Almost all neurotransmitters have receptor subtypes
• Most receptors fall into 2 broad categories: ionotropic receptors or metabotropic receptors

lonotropic Receptors

• lonotropic receptor: fast-acting
• Comprised of several subunits & an ion channel regulated by neurotransmitters binding to specific sites of the receptor
• In resting state: receptor channel is closed
• When neurotransmitter binds to the receptor & activates it, the channel immediately opens & ions flow across the membrane
• When neurotransmitter dissociates from the receptor, the channel quickly closes
• Also called ligand-gated channel receptors
• Some ionotropic receptor channels allow for sodium (Na+) ions to flow into the cell causing depolarization, excitatory response

lonotropic Receptor Channels Continued

• Some ionotropic receptor channels allow for calcium (Ca+) & sodium (Na+)
• Calcium can act as a second messenger
• First-messenger is the initial link in the chain of information transfer from one cell to another (i.e., neurotransmitters or drugs)
• Second-messenger is an intracellular molecule regulated by the first messenger (inside the cell)
• Chloride (Cl-) causes hyperpolarization, inhibitory response

Metabotropic Receptors

• Metabotropic receptors are slow-acting
• Composed of a single large protein in the cell membrane activating G proteins (or G protein-coupled receptor)
• All G proteins operate by 2 mechanisms:
• Stimulating/inhibiting the opening of ion channels in cell membrane
• Stimulating/inhibiting certain effector enzymes in cell membrane
• Increased synthesis/breakdown of a second messenger
• Biochemical/physiological changes in the postsynaptic cell

Allosteric modulation

• Allosteric sites are binding sites on a receptor that modulate the receptor's response to an agonist
• Allosteric modulators are compounds that bind to a receptor site distinct from the main agonist binding site
• Administered alone causes no effect
• They enhance (+ allosteric modulator) or reduce (- allosteric modulator) the effectiveness of an agonist
• Potential therapeutic use: "fine-tune" signaling by the neurotransmitter more subtly than an agonist/antagonist

Pharmacology of Synaptic Transmission

• Drugs enhance the action of a neurotransmitter by reducing its inactivation by blocking an enzyme or a transporter
• Blocking the enzyme involved in its breakdown such as MAO-inhibiting drugs that block MAO
• Blocking the transporter involved in its reuptake
  • Cocaine blocks transporter for DA, NE & 5-HT
  • SSRIs prevent the reuptake of 5-HT
• Drugs act on postsynaptic receptors for a specific neurotransmitter
• Agonists mimic the effects of the neurotransmitter on the receptor such as opioids - opioid receptors
• Antagonists inhibit the effect of the neurotransmitter on the receptor such as antagonists at the D2 receptor subtype of DA in people with schizophrenia