Neuro: Neurons, Nerves & Neurotransmitters

CELLS NEURONS Have exacting glucose and oxygen demands. Require a unique microenvironment created and supported by CSF and glia. Must be exempt from normal immune surveillance (see Blood Brain Barrier). Are permanent with no mitotic potential in adulthood (but limited repair is possible). Universal Components o Cell Body: Large with prominent nucleoli. o Nissl Substance: Found in cell body and dendrites. Absent in axon. o Dendrite o Axon o Synapse: See Synapse Notes. Structural Classification o Unipolar o Pseudounipolar o Bipolar o Multipolar Functional Classification o Afferent o Efferent o Inter

GLIA

Maintain the unique microenvironment required by neurons. Mediate immune process (inflammation and phagocytosis) within the nervous system. Retain mitotic potential in adulthood and facilitate limited neuronal repair. Cell Astrocyte CNS. Location Appearance & Marker GFAP marker. Functions Provides physical support for neurons. Controls microenvironment of neurons (K metabolism, transport of metabolites and waste products). Modulates synaptic transmission (removal of excess neurotransmitter from cleft). Foot processes wrap around BOTH capillaries AND large vessels to form the glia limitans component of the BBB. Undergoes reactive gliosis in response to injury. Myelinates neurons using cell processes. One cell myelinates many axons. Myelin is formed by P0 protein linkages between oligodendrocyte membranes. It is NOT a secretory product.

Oligodendrocyte

75% of CNS glia.

Small dark nuclei, little cytoplasm.

Microglia

5-10% of CNS glia.

Differentiates into macrophage only upon encountering tissue damage or pathogen. Forms multinucleated giant cells upon HIV infection. Secrete growth factors during development. Functional remnants of neural and glial progenitor cells.

Ependymal Cell

CNS.

Schwann Cell

PNS, internal acoustic meatus.

Myelinates neurons using cell body. Many cells myelinate one axon. The gaps in between form the nodes of Ranvier. Myelin is formed by P0 protein linkages between Schwann cell membranes. It is NOT a secretory product. Promotes axonal regeneration after Wallerian degeneration.

NEUROTRANSMITTERS (NTs) Definition: Chemicals that transmit signals from a neuron to a target cell across a synapse. All NTs are synthesized endogenously in the CNS and cannot cross the BBB. Storage & Release: NTs are made and stored in synaptic vesicles in the pre-synaptic neuron. Release is triggered by action potentials OR graded electric potentials. Effect: Each NT either activates stimulatory or inhibitory receptors on the post-synaptic cell. Remember that 80% of neural activity is inhibition (reducing noise). o Many NTs act as hormones (NE/E, 5-HT), but they have completely different receptors and effects in the brain vs. body. Removal: By degradation in the synaptic cleft, recycling/reuptake back to the pre-synaptic neuron via transporters, or removal from the cleft by transporters. Major Classes: Monamines, amino acids, peptides. ALL NTs are derived from amino acids. Catecholamine Synthesis

Serotonin Synthesis

Neurotransmitter Pathways

Pathway Dopamine (DA) Mesocortical Mesolimbic Nigrostriatal Tuberoinfundibular

Location & Synthesis Ventral Tegmental Area, Substantia Nigra Pars Compacta, Nucleus Accumbens: From tyrosine. See catechol syn pathway. [DA] is determined by initial [tyrosine] in the liver. Tyrosine hydroxylase is the rate-limiting step. Vitamin B6 is required. Locus Ceruleus, Lateral Tegmental Area: From tyrosine. See catechol syn pathway. Same as DA above, except vitamin B6 and vitamin C are both required. Dorsal Raphe Nucleus, Pineal Gland: From tryptophan. See serotonin syn pathway. Tryptophan hydroxylase is ratelimiting step. Note that pineal gland synthesizes the hormone melatonin from serotonin. Basal Nucleus of Meynert, Medial Septal Nucleus (and NMJs in the Periphery): From choline and acetate. **Botox works ONLY at NMJ, but tetanus can enter brain via retrograde axonal transport. Major inhibitory NT in brain. From glutamate. Concentrated in nucleus accumbens.

Action D-1R thru D-5R: Reward, cognition, endocrine regulation of prolactin, nausea.

Degradation & Reuptake MAO & COMT: Located in the cytoplasm of postsynaptic neurons. Degrade DA to homo-vanillic acid (HVA), the most abundant waste product in the CNS. DAT: Recycles DA from synaptic cleft back to presynaptic neurons. MAO & COMT: Located in the cytoplasm of postsynaptic neurons. Degrade NE to vanillylmendelic acid (VMA) & E to metanephrine. MAO: Located in the cytoplasm of post-synaptic neurons. Degrades 5-HT to 5 hydroxy-indole acetic acid (5-HIAA). Autoreceptors: Monitor 5HT reuptake. AChE: Degrades Ach in the synaptic cleft. The precursor choline MUST be recycled from the cleft to sustain the Ach response.

STIMULATORY Norepinephrine/ Epinephrine (NE/E)

Adrenergic R: Reward, arousal, vasodilation (2R), vasoconstriction (1R). Remember that 2R inhibits -1R. 5-HTR: Increases mood, satiety, body temp, sleep. Decreases perception of pain (nociception). 5-HT1 and 2 are metabotropic, and 5-HT3 is ionotropic. Nicotinic AChR (VoltageGated, Fast, Stim) & Muscarinic AChR (GProtein, Slow, Stim or Inhib): Learning, shortterm memory, arousal, award. GABA-A: A Cl channel. Neuronal inhibition. GABA-B: Autoreceptors that monitor [GABA].

High in CNS Schizophrenia: Upregulates dopa carboxylase. Amphetamines & Hallucinogens: Upregulate dopa carboxylase. Tourettes: Increases recycling by DAT. Anxiety

Low in CNS Parkinsons: >80% of DA neurons lost by onset of sx. Toxins: Many are analogous to DA and target DA neurons. Depression Depression

Drugs -Methyltyrosine (): Blocks DA syn by tyrosine hydroxylase. Reserpine (): Blocks DA transport by VMAT protein. Amphetamine (): Blocks DA release. Morphine (): Blocks DA feedback to presynaptic neurons. Cocaine (): Blocks DA reuptake. Pargyline (): Blocks degradation by MAO. Tyramine (): Endogenous DA/NE/E releasing agent that cannot cross the BBB. Results in peripheral sym sx. Found in fermented foods (wine, cheese). Normally degraded by MAO. Reserpine (): Blocks 5-HT transport by VMAT protein. SSRIs (): Block 5-HT reuptake.

STIMULATORY Serotonin (5-HT)

STIMULATORY Acetylcholine (ACh)

Hallucinogens: 5HT2R agonists. MDMA (Ecstasy): Stimulates 5-HT release & depletes 5-HT reserves. Anxiety REM Sleep

Depression: Low [5-HT]. OCD: Low [5-HT]. Bipolar: Mutation of tryptophan hydroxylase. Alzheimers Huntingtons

N: STIMULATORY M: STIM or INHIB GammaAminobutyric Acid (GABA)

Glia: Degrade GABA. This is the only NT made by one cell type (GABA neuron) but degraded by another (glia). GLY1 & GLY2: Transporters in astrocytes and neurons. Astrocytes degrade Gly, while neurons recycle it. Glia: Assist in Glu reuptake.

Anxiety Huntingtons

INHIBITORY Glycine (Gly)

Major inhibitory NT in interneurons of spinal cord. From serine. Major excitatory NT in brain. Concentrated in striatum, hippocampus, cerebellum.

Gly-R: A Cl channel. NMDA: Allosterically inhibited by Gly. NMDA: Mg and voltagegated Na/Ca influx and K efflux channel. Requires Gly co-agonist. Synaptic plasticity for memory & learning. AMPA: Ca ion-gated Na influx and K efflux channel.

INHIBITORY Glutamate (Glu)

Hyperekplexia (Startle Disease): Very low GLY-R affinity.

Physostigmine, Selenophosphates (): Inhibit AChE to potentiate ACh response. Nicotine (): N-AChR agonist. Curare (): N-AChR antagonist. Muscarine (): M-AChR agonist. Atropine (): N-AChR antagonist. Scopolamine (): Comp M-AChR inhibitor. Tetanus Toxin (): Blocks ACh release. Baclofen (): GABA-B agonist. Bicuculline ():GABA-A antagonist. Competes with GABA for active site. Benzodiazapines (): GABA-A agonist. Barbituates (): GABA-A agonist. Alcohol (): GABA-A agonist. Strychnine (): Gly-R antagonist Picrotoxin (): Gly-R inhibitor. Antidote for barbiturate poisoning. PCP (): Competes with Mg binding on NMDA.

STIMULATORY