Neurotransmitter Synthesis and Degradation

Neurotransmitter Systems

• Three major classes of neurotransmitters include amino acids, peptides, and amines.
• Amino acid neurotransmitters: glutamate, GABA, glycine.
• Peptide neurotransmitters: peptides.
• Amine neurotransmitters: acetylcholine (ACh), norepinephrine (NE), epinephrine/adrenaline, dopamine (DA), and serotonin (5-HT).

Synthesis and Degradation of Neurotransmitters: Cholinergic System

• The cholinergic neurotransmitter system utilizes acetylcholine (ACh).
• Precursors: choline + acetyl CoA.
• Enzyme: choline acetyltransferase (ChAT).
• Choline is the rate-limiting step in ACh synthesis.
• Vesicular acetylcholine transporter (VAChT) transports ACh.
• Acetylcholinesterase (AChE) degrades ACh.
• Reuptake is done via the choline transporter (ChT).

Synthesis and Degradation of Neurotransmitters: Catecholaminergic System

• Catecholaminergic neurotransmitters are monoamines
• Tyrosine is a precursor for dopamine, norepinephrine, and epinephrine.
• All catecholamines have a conversion from Tryosine to DOPA
• Tyrosine hydroxylase (TH) is the rate-limiting step.
• Parkinson's Disease involves the degeneration of dopamine-producing neurons in the substantia nigra.

Synthesis and Degradation of Neurotransmitters: Serotonergic System

• The serotonergic neurotransmitter system utilizes serotonin.
• Tryptophan is the precursor.
• Tryptophan hydroxylase is the enzyme.
• 5-HTP is an intermediate.
• 5-HTP decarboxylase is an enzyme.
• Tryptophan precursor is the rate-limiting step.

Synthesis and Degradation of Neurotransmitters: Amino Acidergic System

• The amino acidergic neurotransmitter system involves glutamate and GABA.
• Glutamate is converted to GABA by glutamic acid decarboxylase (GAD).
• GAD (glutamic acid decarboxylase) is the rate-limiting step.

Retrograde Messengers

• Endocannabinoids are manufactured on demand (Ca2+), small, permeable, and bind to CB1 receptors on the presynaptic cell.
• Nitric oxide (NO) diffuses and spreads to lots of different neurons.
• CB1 receptors are "Heteroreceptors" because the presynapse doesn't produce endocannabinoids.
• Autoreceptors are presynaptic receptors that bind neurotransmitters synthesized in the same presynapse.

Removal of Neurotransmitters from Synaptic Cleft

• Diffusion: Transmitters diffuse away from synapse
• Reuptake: Re-enters presynaptic axon terminal via specific transporter proteins
  • Na+-dependent transporters
  • Astrocytes
• Degradation: Enzymatic destruction inside terminal cytosol or synaptic cleft
  • ACh: acetylcholinesterase
  • Catecholamines + 5-HTP: Monoamine oxidase

Receptor Subtypes

• Same neurotransmitter can bind to different receptor proteins (e.g., ACh binds to nicotinic and muscarinic receptors).
• The effect of a neurotransmitter (NT) is determined by the postsynaptic receptor.

Categories of Cellular Receptors

• Types of receptors and sub-types include Ionotropic (Channel-linked), Metabotropic (G-protein-coupled), Enzyme-linked, and Intracellular receptors.

Ionotropic Receptors

• The structure is pentameric; usually has 5 protein subunits.
• Each protein subunits express 4 transmembrane domains
• Nicotinic ACh muscle receptor is a2byd.
• Nicotinic ACh neuron receptor is a3b2.
• Span of effect is short-spread.
• Activation: Channel opens.
• Selective: Yes.
• Regulate ionic current: Yes.
• Speed: faster than metabotropic.

Ionotropic Receptors:Glutamate Receptors

• Types of glutamate receptors: AMPA, Kainate, and NMDA
• Structure: Tetrameric.
• AMPA or Kainate + Glu: Na+ enters and K+ leaves.
• NMDA + Glu at -65 mV: receptor is blocked by Mg2+.
• NMDA + Glu at -30 mV: Mg2+ block moves, and Na+ and Ca2+ enter.

GABA-gated and Glycine-gated Channels

• GABA mediates most synaptic inhibition in the CNS.
• Glycine mediates non-GABA synaptic inhibition.
• These channels bind ethanol, benzodiazepines, and barbiturates.

Metabotropic or G-protein Coupled Receptors

• Structure: One polypeptide with 7 membrane-spanning regions.
• G-protein: 3 subunits (Ga has GDP).
• Span of effect: Wide-spread.
• Activation: Effector systems.
• Speed: Slower than ionotropic, but amplified effects.

Metabotropic Receptors

• Activated metabotropic receptors activate G-proteins that activate 'effector' proteins.
• Types of proteins:
  • G-protein-gated ion channels (Shortcut pathway; Gby to K+).
  • Second messenger enzymes (“downstream enzymes” through Ga).

2nd Messenger Systems

• Stimulation and inhibition of adenylyl cyclase & cyclic nucleotide cycle uses G-proteins:
  • Binding of norepinephrine to the beta receptor activates Gs, which activates adenylyl cyclase, generates cAMP and downstream enzyme protien kinase A
  • Binding of norepinephrine to the a2 receptor activates Gi, which inhibits adenylyl cyclase.

2nd Messenger Affecting Intracellular Ca2+ Release: Lipid Cascade

• G-protein-coupled receptors stimulate the enzyme phospholipase C (PLC), which splits PIP2 into DAG and IP3; DAG stimulates protein kinase C (PKC);IP3 stimulates the release of Ca2+ from intracellular stores; Ca2+ go on to stimulate various downstream enzymes.

Vesicular Packing

• Peptides, Amino Acids & Amines are packed into vesicles.
• Peptides: made in soma, transported in secretory granules.
  • Secretory granules
  • Dense core vesicles
  • Golgi apparatus
• Amino Acids and Amines:
  • Synaptic vesicles: Small clear vesicles
  • Vesicular transporter proteins on vesicles allow specific NT inside
  • ATP-powered proton pump creates a gradient inside the vesicle.

Vesicular and Reuptake Transporters

• Vesicular Transporters trade H+ for NT.
  • include Vesicular glutamate transporter (VGLUT), Vesicular GABA transporter (VGAT) Vesicular acetylcholine transporter (VACHT), and Vesicular monoamine transporter (VMAT).
• Reuptake Transporters trade 2Na+ for NTs.
  • Excitatory amino acid transporter (EAAT)
  • GABA transporters (GAT); Glycine transporter (GlyT)
  • Choline transporter (ChT)
  • Dopamine active transporter (DAT); Norepinephrine transporter (NET)
  • Serotonin transporter (SERT)

Neurotransmitter Categories

• Small Molecule Neurotransmitters: Amino Acids
  • Glutamic acid (glutamate): principal excitatory neurotransmitter.
  • Gamma-aminobutyric acid (GABA): principal inhibitory neurotransmitter; degeneration of basal ganglia - Huntington's chorea.
• Small Molecule Neurotransmitters: ACh
  • presynaptic terminal: Acetyl CoA + Choline -(Choline acetyltransferase (ChAT)> ACh +CoA
  • synaptic cleft: ACh -(Acetylcholinesterase)> Acetic acid + Choline
• Large Molecule: Neuropeptides
  • Very diverse with variable structures and functions
  • made in soma, transported in secretory granules, away from active zone of presynaptic terminal
  • requires repetitive action potentials to build up Ca2+ to slowly release: Examples Endorphins (endogenous opioids; pain relief, reward and reinforcement), Dynorphin and Enkephalins.
• Atypical Neurotransmitters:
  • are small molecules with characteristics unique from other neurotransmitters - often called neuromodulators.
  • Not classical transmission – released as made in the soma or dendrite (no storage) that can diffuse freely across cell membranes to neighboring neurons.
  • Examples are nitric oxide, carbon monoxide and endocannabinoids: anandamide, 2-AG.

Neurotransmitter Drug Actions and Locations of Receptors

• Drug actions can mimic or enhance neurotransmitters through several mechanisms:
  • Precursor action [ex. L-DOPA (Levodopa) to make dopamine], cause synaptic release [ex - Block Widow venom], agonist: Activate or Enhance Post-synaptic Receptors, re-uptake blockers (ex - cocaine, Ritalin, Adderall).
• Drug actions can also block or decrease action of neurotransmitters:
  • Inactivate synthesis enzyme (ex. - PCPA (para-chloro-phenylalanine) blocks serotonin synthesis), prevent synaptic release, prevent presynaptic neurotransmitter uptake into vesicles (ex. Reserpine for catecholamines) and antagonist which blocks post-synaptic receptor.
• Auto receptors are found on presynaptic membrane that dampens further neurotransmitter release.

Stimulants And Toxins

• Dopamine (DA) and Norepinephrine (NE) actions are limited by selective transporter RE-UPTAKE
  • Amphetamine and Adderall block re-uptake, reverses transport, and internalizes transporter
  • Cocaine & Ritalin specifically block re-uptake, prolonging the duration of action
• Toxins affecting neurotransmitter action:
  • Botulinum toxin: Blocks ACh release by cleaving v-SNARES and t-SNAREs (paralysis).
  • Tetanus toxin:Blocks GABA/Glycine release by cleaving synaptobrevin in interneurons which in turn causes extreme muscle spasms, commonly in the spinal cord.

Divisions of the Nervous System: Overview And Function

• The sensory division carries sensory signals from the organs to the CNS.
• The motor division initiates voluntary movement and is somatic.
• The sympathetic nervous system (SNS) is arousing with fight or flight behaviors
• The parasympathetic nervous system (PSNS) regulates calming and rest and digest functions

divisions of the Nervous System: Peripheral Nervous System (PNS)

• All preganglionic neurons use acetylcholine (ACh)
• SNS postganglionic neurons use noradrenaline (NE)
• PSNS postganglionic neurons use acetylcholine (ACh)

Amnesia

• Retrograde Amnesia pertains to the loss of declarative memories before a trauma.
• Anterograde Amnesia characterizes being unable to form new declarative memories following a trauma.

Anatomy Of The Eye

• Sclera: The white tissue of the eye and a tough wall
• Cornea: Transparent outer covering of the eye, bends light and is responsible for most of the refraction
• Iris: Pigmented ring of muscles within the cornea Pupil: Adjustable opening in the iris that controls the amount of light that enters the eye and series of transparent onion-like layers (cataracts-diabetes, UV, etc.);
• Lens: additionally refracts light through fine-tuning with a focus
• Ciliary Muscles: changes the shape of the lens for accomodation
• Light travels through the cornea, the aqueous humor, the iris, the lens, the vitreous humor and lastly the retina.
• Everything is "out of the way" so that light directly hits the cones which allows for detailed vision

Photoreceptors

• Rods (120 million): Rod shaped, for B&W vision, can be used with dim light, lots in periphery, are not detailed or precise
• Cones (6 million): Cone shaped, allow for bright light and color vision, most in fovea and detailed/precise
• Photoreceptors are depolarized in the dark when high concentrations of cGMP bind to Na+ channels and keep photoreceptor depolarized.
  • Rhodopsin absorbs light, an active G-protein activates Phosphodiesterase that breaks down cGMP to GMP which reduce the ability to open sodium channels and results in the hyperpolarization of the photoreceptor

Cells in the Retina

• Photoreceptors:
  • NO action potentials (graded potentials), Dark: depolarized → inhibits Bipolar cells, Light: hyperpolarized → inhibition removed
• Bipolar cells:
  • NO action potentials (graded potentials), Dark: hyperpolarized→ inhibited, Light: depolarized → excited
• Retinal Ganglion cells:
  • APs sent through optic nerve, Dark: not excited, 3Hz basal activity, Light: excited → more APs
• Retina Disorders mostly affects the peripheral and cones such as through macular degenration or retinits pigmentosa

Visual Pathways

• Nasal visual field crosses over at the optic chiasm.

Pathway Cuts and Vision Deficits

• Cut Optic Nerve: Loose visual information in the same eye
• Cut Optic Chiasm: No peripheral vision as nasal visual input is lost
• Cuper Optic Tract: Lose one visual field from the other side

Sense Of Hearing

• Organ of Corti which exists between exists between the The Organ of Corti between the tectorial and basilar membranes is part of the the Inner ear
  • The cycle of sound can be measured by finding the distance between successive compressed patches of air
    • Audible variations in air pressure are categorized into Frequency, intensity and Cycle of sound.

Ear Structure and Neural Transduction

• Outer ear, Middle ear and Inner ear
• The pathway starts with Sound waves tympanic membrane
  • Then that amplifies through the Ossicles membrane of oval window which that then move to the that movement of oval window becomes cochlear fluid, activating the hair cell.
  • That hair cell then activates action potentials to the brain in the spiral ganglion neuron
• Components Of The Middle Ear
  • The the sound force must be amplified with Malleus then the icus and lastly by the Stapes
  • The Attenuation reflex: when onset of large sound can be reduced with tensor tympani and stapedius muscle contraction

The Inner Ear

• Cochlea with 3 chambers, 3 membraness with the Organ of Corti
  • The scale vestibuli and scale tympani have perylymph with low K. high na
  • Scala media contain endolymph which has high k and low na
• Specialized epithelial cells form synapses on neurons whose soma is in spiral ganglion with 2 types of hair cells:
  • (auditory receptors) where outercilia extends into tectorial membrane and inner cilia extends just below tectorial membrane
  • Spiral Ganglion Is is the is the
  • Then activate action potentials to the brain and inner hair cells that extend beyond tectorial membrane and support that cell is the rods of corti
• Hair Cell Activation:
  • The cilia tips allow mechanincally gated opening with endolymph which is used to stretch tips with k which will polairze that cell allowing CAtt lead to release which causes Glutamate a neurit from spirial gangion to release an action potential

Sound Encoding

• Intensity/Amplitude (loudness) is linked to Firing frequency and Number of cells activated (sending action potentials)

• Sound is also encodes using frequecy:

  • Tonotopy / Place coding is located with base is higher than those appex

Sound Stimulus Encoding

• Tonotopy/Place-coding: is how different frequencies vibrate basilar membrane at different spots (200 - 20K Hz)
• Phase locking encodes action potientals which codes frequancy with a consistent wave (low frequency 20-5K hz

Other Aspects In Senses

• Sound localisation codes horizontal planes in interaural time and interaural level as well as vertical plane echo localisation with pinna reflections
• Semicircular: three channels that know wether you nodding your head or turnning at shoulder
• Push Pulls : can be known how you turn
• Vestibular pathways

Vestibular System

• Balance, equilibrium, posture; head, body, eye movement are all dependent upon the semicircular and other balanc
• It also is associated in the brain via the 8th cranial nerve to the spinal code for medulla and balances

Otolith Organs

• Dectects changes to head angled the Macula is what can tilt heads allowing stereocilia movements to the cillium to increase the potential and the apposite is in decreasing otential The Semicircular Carina, allow otoliths to have semiciruclilar in channels but push and pull activation from left ot right.
• All signals for posture, reflex etc are tied to the thalamus in the cortex and is also tied to the basal brain