Neurobiology Quiz 2

Synthesis of Histamine

Synthesis of Histamine

• Histamine is synthesized into Histamine via the enzyme Histidine decarboxylase

• Histamine loaded into vesicles by VMAT (vesicle monoamine transporter)

• Binds postsynaptically to GPCR (H1, H2, H3, H4)

• Degraded intracellularly by monoamine oxidase (MAO)

Function of Histamine

Mediates allergic reactions (responsible for itch sensations), involved in vestibular function, and helps regulate gastric secretions.

Histamine antagonist

• Anti-histamines: Benadryl, diphenhydramine

• Motion sickness medication

• Peptic ulcers

Synthesis of Serotonin

• Tryptophan is synthesized into 5-Hydroxytryptophan via the enzyme Tryptophan-5-hydroxylase, then synthesized into Serotonin via the enzyme Aromatic L-amino acid decarboxylase.

• Serotonin is loaded into vesicles by VMAT, then binds postsynaptically to both ionotropic 5-HT3 receptors and metabotropic 5-HT1-7 receptors.

• Taken up by a presynaptic terminal via Serotonin Transporter (SERT).

• Degraded intracellularly by monoamine oxidase (MAO)

Serotonin Receptors:

More metabotropic (5HT 1, 2, 4, 5, 6, 7) than ionotropic (only 5-HT 3), the pore is a non-selective cation channel which mediates excitatory signals.

Serotonin Function:

Regulates sleep and wakefulness (levels rise as ambient light levels fall, bringing on sleep), circadian rhythms, regulates emotional state, and mediates satiety.

Serotonergic System:

• SSRI (Selective Serotonin Reuptake Inhibitor) keeps serotonin in synapse for longer

• MAOI (Monoamine Oxidase Inhibitors) keep serotonin from being broken down

• Anti-depressants (Prozac)

• Metabotropic 5-HT receptor agonists include anti-depressants, anxiolytics, antipsychotics, appetite suppressants, psychedelics, hallucinogens (LSD, mescaline, psilocybin)

• Ionotropic 5-HT receptor antagonist include Anti-emetics (Zofran)

Purines:

• ATP is present in all synaptic vesicles and is therefore a co-transmitter.

• ATP is excitatory through the ionotropic P2X receptors

• Multiple effects through metabotropic P2Y receptors

• Adenosine is not in synaptic vesicles, rather is a metabolite of ATP produced in the synapse

• Adenosine is inhibitory through metabotropic adenosine receptors.

• Adenosine slows the heart rate and has a sedative effect on the brain, which is why caffeine inhibits adenosine receptors, making caffeine a stimulatory antagonist of adenosine.

Neuropeptides:

• Always start with Tyr-Gly-Gly-Phe-Met

• Pre-propeptide is the initial product of translation and contains a signal sequence that is removed in the ER

• Propeptide is packaged into vesicles after traversing the Golgi

• Active peptides are produced by proteolytic cleavage of propeptides within vesicles.

Opioid peptides:

• Leucine enkaphalin, a-Endorphin, and Dynorphin A are all natural analgesics.

• Opioid peptides are the endogenous ligands for receptors that mediate responsiveness to opioids (are made from our own bodies)

• Bind to metabotropic receptors

Endocannabinoids:

• Endogenous ligands of cannabinoid receptors mediate the effects of THC, a psychoactive component of marijuana.

• Produced post-synaptically from membrane phospholipids.

• Cause a prolonged depolarization of post-synaptic cells, opens VG Ca2+ channels, which trigger a signaling cascade that cleaves the endocannabinoids from the post-synaptic surface, SIGNALS POST TO PRE SYNAPSE

• Functions pre-synaptically via feeding back on the pre-synaptic terminal where they bind to cannabinoid receptors (CB1).

• CB1 activation triggers signaling that decreases further neurotransmitter release, negative modulation of synaptic transmission (tells it to shut up)

Endocannabinoid production:

Phosphatidylethanolamine is synthesized into N-Archidonoyl phosphatidylethanolamine via the enzyme N-Acyltransferase, then synthesized into Anandamine via the enzyme Phospholipase D.

Animal Development:

• Haploid sperm and haploid egg are fertilized to make diploid zygote

• Cleavage is rapid mitotic cell division to form a blastocyst

• Gastrulation is the rearrangement of cells into a 3-layered gastrula comprised of 3 germ layers, the ectoderm, mesoderm, and endoderm

• Organogenesis is the formation of organ systems via neurulation

Neural Induction (Neurulation)

• Signals the notochord to become the neural plate (part of the ectoderm) comprised of columnar epithelium

• Neural plate bends to form the nerual groove, the most ventral part of the groove is the floorplate, the outermost edges are the neural folds, and the cells of the neural folds will become the neural crest.

• The neural folds fuse to form the enclosed neural tube, which occurs toward the anteroir end of the embryo first, which becomes the brain. The posterior region becomes the spinal cord.

• Some neural crest cells become components of the peripheral nervous system.

Somites:

Blocks of mesoderm lateral to the neural tube that give rise to vertebrae, muscle, and dermis of the skin.

Migratory cells of the neural crest:

As folds approach each other at the midline, cells exit the epithelium and become migratory neural crest cells. These cells turn into sensory ganglia, autonomic ganglia, adrenal neurosecretory cells, or melanocytes.

Properties of an Early Neural Tube:

• Simple epithelium, pluripotent neural stem cells, the spaces will become ventricles of the brain and spinal canal, which contain cerebrospinal fluid.

• Stem cell daughters can differentiate into multiple specialized cell types such as radial glial cells, neurons, etc.

3-Vesicle Stage:

1. Prosencephalon → Forebrain, most anterior

2. Mesencephalon → Midbrain

3. Rhombencephalon → Hindbrain, most posterior

• Cephalic and cervical flexures create curves.

5-Vesicle Stage:

1. Prosencephelon → Telencephalon (cerebrum) and Diencephalon (thalamus, hypothalamus, and optic vesicles)

2. Mesencephalon (Midbrain)

3. Rhombencephalon → Metencephalon (pons and cerebellum) and Myelencephalon (medulla oblongata)

• Pontine flexure adds more curve between meten. and myelen.

Morphogenesis:

The generation of increasingly complex and specialized shapes in an embryo over developmental time. Early segmentation of embryo governed by Hox genes.

Hox genes:

• Encode transcription factors that activate transcription of specific subsets of other transcription factors.

• TFs are proteins that bind to a regulatory element, expressing a gene.

• Hox genes are only expressed in the hindbrain and spinal cord.

• Inductive signals turn Hox genes on

Induction:

• Roofplate cells express unique TFs due to exposure to surface ectoderm, which induce neighboring neural tube cells to express a different subset of TFs.

• Notochord releases signals that lead to floorplate differentiation

• Floor plate cells then induce neighboring cells to express a different subset of TFs.

Stem Cell Concept:

Oocyte has the potential to divide and give rise to all of the differentiated cell types of the adult organism, making it totipotent.

Embryonic stem cells:

From the inner cell mass of a blastocyst-staged embryo, pluripotent, which means they can give rise to many cells, but not the trophoblast.

Induced pluripotent stem cells:

A normal cell can be exposed to 4 TFs that reverse them to a stem-cell like phenotype.

Sonic Hedgehog (Shh)

• Early, expressed in notochord and secreted to induce floorplate differentiated

• Later, inactivates Gli3 which keeps certain TFs on.

Noggin and Chordin:

• Expressed in notochord

• Inhibits bone morphogenetic proteins (BMPs) that keep some TFs on

Migrating neurons:

• Radial glial cells are the first to form in the VZ.

• Extends processes to connect to the lumenal surface and pial surface

• Glial guidewires lead the migrating neuron to where it is meant to detach.

• Radial migration is stopped when Reelin is detected at the radial glial endfoot.

Mutations affecting neuronal migration:

• Reelin mutation produces fewer neurons which disrupts the formation of the folds (sulci and gyri) and produces large vesicles

• Doublecortin (DCX) mutation is a much more severe form of a reelin mutation, leads to lissencaphy (smooth brain)

Identity of neural crest:

While moving, cells are exposed to different chemicals, changing the cells outcome.

Retinogeniculocortical pathway:

• Optic nerves cross or stay lateral depending on the retina being stimulated (nasal retina crosses, temporal retina does not), stimulus travels to the lateral geniculate nucleus (LGN), then to the occipital lobe in the striate cortex.

Neuroblasts:

Dividing cells of the ventricular zone, gives rise to neurons and glia. VZ is 1 layer thick (Pseudostratified)

Vertical vs Horizontal cleavage:

• If divided horizontally, one cell stays stem cell, one becomes post-mitotic and begins moving. If divided vertically, both stay stem cell.

• Depends on the distribution of 2 TFs, notch-1 and numb

  • Notch-1 accumulates on the pial side of the cell

  • Numb accululates on the VZ side

• In vertical cleavage, both daughter cells contain both TFs, presence of numb dictates the fate of a cell as a neuroblast

• In horizontal cleavage, the top cell has notch-1, making it post-mitotic.

What determines the fate of a cell that is post-mitotic?

1. Age

2. Position within the VX

3. Environment of the VZ (what TFs are present)

Differentiation of pyramidal neurons:

• Post-mitotic cell extends neurites

• One neurite becomes the axon, others become apical or basal dendrites

• Semaphorin 3A (protein) from marginal zone repels axon but attracts apical dendrites, creating a polarization.

Genesis of connections:

• Guidance cues guide axons with interactions between surface molecules of the axon, ECM, or diffusible molecules.

• Can be chemoattractants or chemorepellants

The Growth Cone:

• An exploratory extension

• Forms attachments with permissive molecules to pull the axon.

• Lamellipodia is the “palm”

• Filopodia is the “finger”

Interactions between axons:

• Axons often travel as bundles or fascicles

• Fasciculation requires interaction between CAMs (cell adhesion molecules) on adjacent axons that are expressed on the surface of the growth cone

• Integrins interact with laminin in extracellular matrix.

Synapse formation in NMJ:

1. Presynaptic terminal secretes agrin and neuregulin

2. Agrin binds to MuSK (muscle specific kinase) on a muscle fiber

3. MuSK interacts with rapsyn

4. Rapsyn causes AChRs to cluster in the post synaptic density

5. Neuregulin leads to increased expression of AChRs in muscle fiber

6. Muscle fiber secretes laminin into cleft to provide sites of attachment for presynaptic terminal

7. Synaptic vesicle containing ACh accululate in presynaptic terminal.

Naturally occuring cell death (NOCD):

Too many neurons are made, so the ones that do not have target neurons are programed to apoptosis.

The neurotrophin hypothesis:

• Target tissue produces a factor neurotrophin required for survival of neurons, but only in limiting quantities. Only the neurons that gain access to this factor will survive.