Hodgkin cycle Synaptobrevin Syntaxin Synaptotagmin. Temporal dispersion of compound action potentiol Why does botulinum toxin cause dry mouth? Types of Toxins, Types of venom produced by different species like fish, snake etc. Neuropraxia. Axonotmesis. Neurotmesis. Sunderland classification. Seddon classification. Why is recovery different in each? Explain opisthotonus. SNARE protiens. In botulinum toxicity, which snare protien is affected? Lambert-Eaton Syndrome: Which calcium channels are affected in it? Myasthenia Gravis: Why are ocular muscles first affected? Choline recycling. Rate-limiting step in acetylcholine synthesis. Saxitoxin mechanism. Tetrodotoxin mechanism. Explain cable properties of neurons. Why is conduction slower in diabetes? Tensilon test. Ice pack test. Curare mechanism. Subliminal fringe. Summation. Facilitation. Occlusion. Fast vs slow axonal transport. Multiple Sclerosis physiology. Guillain-Barré syndrome physiology. Why are tendon reflexes absent in peripheral neuropathy? Diseases affecting myelin. Difference between Goldman and Nernst equation.Hodgkin cycle Synaptobrevin Syntaxin Synaptotagmin. Temporal dispersion of compound action potentiol Why does botulinum toxin cause dry mouth? Types of Toxins, Types of venom produced by different species like fish, snake etc. Neuropraxia. Axonotmesis. Neurotmesis. Sunderland classification. Seddon classification. Why is recovery different in each? Explain opisthotonus. SNARE protiens. In botulinum toxicity, which snare protien is affected? Lambert-Eaton Syndrome: Which calcium channels are affected in it? Myasthenia Gravis: Why are ocular muscles first affected? Choline recycling. Rate-limiting step in acetylcholine synthesis. Saxitoxin mechanism. Tetrodotoxin mechanism. Explain cable properties of neurons. Why is conduction slower in diabetes? Tensilon test. Ice pack test. Curare mechanism. Subliminal fringe. Summation. Facilitation. Occlusion. Fast vs slow axonal transport. Multiple Sclerosis physiology. Guillain-Barré syndrome physiology. Why are tendon reflexes absent in peripheral neuropathy? Diseases affecting myelin. Difference between Goldman and Nernst equation. give answer for above mentioned questions for mbbs 1st year exam physiology

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MBBS 1st Year Physiology - Complete Topic Notes

1. Hodgkin Cycle (Positive Feedback Cycle of Depolarization)

The Hodgkin cycle (also called the Hodgkin-Katz cycle or regenerative cycle) explains why action potential depolarization is explosive and self-sustaining:

Membrane depolarizes slightly above threshold
Voltage-gated Na+ channels open → Na+ rushes in
Inside becomes more positive → more depolarization
More depolarization → more Na+ channels open
This is a positive feedback loop - it continues until all fast Na+ channels are open (peak ~+35 mV)

This is why the action potential is all-or-none - once threshold is crossed, the cycle is self-propagating. It stops because Na+ channels rapidly inactivate (h-gates close) and K+ channels open causing repolarization.

2. Synaptobrevin, Syntaxin, Synaptotagmin - SNARE Proteins

SNARE Proteins Overview

SNARE = Soluble NSF Attachment Receptor proteins. They are the molecular machinery for synaptic vesicle fusion with the presynaptic membrane.

Protein	Location	Type	Also Known As
Synaptobrevin	Vesicle membrane	v-SNARE	VAMP (Vesicle-Associated Membrane Protein)
Syntaxin-1	Plasma membrane	t-SNARE	-
SNAP-25	Plasma membrane	t-SNARE	Synaptosomal-associated protein 25 kDa
Synaptotagmin	Vesicle membrane	Ca²+ sensor	-

Mechanism of Vesicle Fusion:

Vesicle docks near active zone
Synaptobrevin (v-SNARE) zippers with Syntaxin + SNAP-25 (t-SNAREs) forming a tight 4-helix bundle
This pulls vesicle membrane toward plasma membrane
Synaptotagmin acts as the Ca²+ sensor - when Ca²+ floods in via voltage-gated Ca²+ channels, synaptotagmin binds Ca²+ and triggers the final fusion step
Vesicle membrane merges with plasma membrane → neurotransmitter released into synapse

Medical Physiology - the SNARE complex: synaptobrevin (VAMP), syntaxin-1, and SNAP-25 mediate vesicle fusion; synaptotagmin is the Ca²+ sensor

3. SNARE Proteins in Botulinum Toxicity

Botulinum toxin is a zinc-dependent protease (metalloprotease) that cleaves SNARE proteins:

Toxin Serotype	Target SNARE Protein Cleaved
Type A, E	SNAP-25
Type C	Syntaxin AND SNAP-25
Type B, D, F, G	Synaptobrevin (VAMP)

Result: Vesicle fusion cannot occur → no acetylcholine release at neuromuscular junction → flaccid paralysis.

Most clinically used (Type A - Botox): cleaves SNAP-25, preventing SNARE complex assembly.

4. Why Does Botulinum Toxin Cause Dry Mouth?

Botulinum toxin blocks all cholinergic synapses, not just the neuromuscular junction. Salivary glands are innervated by parasympathetic cholinergic fibers (from CN VII and CN IX). When botulinum toxin blocks ACh release at these glands:

No muscarinic (M3) receptor stimulation
No salivary secretion
Result: Xerostomia (dry mouth)

This is also why botulinum toxicity produces other autonomic features: blurred vision (loss of pupil constriction/accommodation), constipation, urinary retention, anhidrosis.

5. Temporal Dispersion of Compound Action Potential (CAP)

A Compound Action Potential is the summated electrical response of many nerve fibers firing together. Different fibers within a nerve have different diameters and myelination → different conduction velocities.

Temporal dispersion means that when you stimulate proximally vs distally, the CAP recorded at a distant point becomes:

Wider (longer duration)
Lower in amplitude
Polyphasic

This happens because fast fibers (Aα) arrive early, slow fibers (Aδ, C) arrive later - they "spread out" over time. The more distal the recording point, the greater the dispersion.

Clinical significance: Increased temporal dispersion on nerve conduction studies = demyelinating neuropathy (e.g., Guillain-Barré, CIDP). In axonal neuropathies, you see reduced amplitude but less dispersion.

6. Types of Toxins / Venoms

Classification of Toxins:

By Source:

Neurotoxins, cardiotoxins, cytotoxins, hemotoxins, nephrotoxins

Snake Venoms:

Snake Type	Venom Components	Effect
Elapids (cobras, kraits, mambas)	α-bungarotoxin, neurotoxins	Postsynaptic ACh receptor block → flaccid paralysis
Vipers/Pit vipers (Russell's viper, rattlesnakes)	Hemotoxins, phospholipases, proteases	Coagulopathy, tissue necrosis, hemolysis
Cobras	Cytotoxins + neurotoxins	Tissue necrosis + paralysis
Sea snakes	Myotoxins	Rhabdomyolysis

Fish Venoms/Toxins:

Fish/Source	Toxin	Mechanism
Puffer fish (Fugu)	Tetrodotoxin (TTX)	Blocks voltage-gated Na+ channels
Red tide/Shellfish	Saxitoxin (STX)	Blocks voltage-gated Na+ channels
Stonefish	Stonustoxin	Hemolytic, cardiovascular collapse
Stingray	Phosphodiesterases	Pain, necrosis
Ciguatera fish	Ciguatoxin	Activates Na+ channels (prolonged opening)

Spider/Scorpion:

Black widow spider: α-latrotoxin → massive ACh release (presynaptic)
Scorpion: Slows Na+ channel inactivation → prolonged depolarization

7. Nerve Injury Classification

Seddon Classification (3 types):

Grade	Name	Pathology	Recovery
I	Neuropraxia	Focal demyelination; axon intact	Complete, weeks to months
II	Axonotmesis	Axon disrupted; endoneurium intact	Good; ~1 mm/day regeneration
III	Neurotmesis	Complete nerve trunk disruption	Poor; surgery needed

Sunderland Classification (5 degrees):

Degree	Corresponds to Seddon	Pathology
1st	Neuropraxia	Conduction block; all structures intact
2nd	Axonotmesis	Axon disrupted; endoneurium intact
3rd	Axonotmesis (worse)	Axon + endoneurium disrupted; perineurium intact
4th	Neurotmesis (partial)	Axon + endo + perineurium disrupted; epineurium intact
5th	Neurotmesis (complete)	Complete nerve transection

Why Is Recovery Different in Each?

Neuropraxia (1st degree): Axon is intact. Remyelination occurs locally. No Wallerian degeneration. Full recovery in 6-12 weeks. No need for axon regrowth.
Axonotmesis (2nd/3rd degree): Axon disrupted → Wallerian degeneration distally. But the endoneurial tube (basement membrane guidance channel) is intact → regenerating axon sprouts follow the correct path. Recovery rate = ~1 mm/day (or 1 inch/month). Recovery is good but incomplete in 3rd degree.
Neurotmesis (4th/5th degree): All supporting structures disrupted → regenerating axons have no guidance. Axons sprout randomly → neuroma formation, misdirection. Recovery is poor without surgical repair.

Key concept: The endoneurial tube acts as a "guidance railway" - if it is intact, regenerating axons can find their target. If disrupted, they cannot.

8. Opisthotonus

Opisthotonus is a severe involuntary spasm in which the body is arched backward with the head thrown back, the neck hyperextended, and the spine arched - supported only on the heels and back of the head.

Cause: Unopposed extensor muscle spasm due to loss of inhibitory interneuron (Renshaw cell) activity or disinhibition of motor neurons.

Main Causes:

Tetanus (Clostridium tetani) - tetanospasmin blocks glycine and GABA release from Renshaw cells and inhibitory interneurons → unopposed excitation of motor neurons
Strychnine poisoning - blocks glycine receptors (similar to tetanus physiology)
Meningitis/meningoencephalitis - extensor rigidity from meningeal irritation
Severe hypoxic brain injury in neonates
Severe hyponatremia

In tetanus specifically: Tetanospasmin travels retrograde via motor neurons to the spinal cord and brainstem, where it cleaves synaptobrevin (VAMP) in inhibitory interneurons → blocks GABA and glycine release → extensors dominate → opisthotonus, risus sardonicus, trismus.

9. Lambert-Eaton Syndrome - Calcium Channels

P/Q-type voltage-gated calcium channels (VGCCs) are affected.

Specifically: antibodies target Cav2.1 (P/Q-type) presynaptic calcium channels at the neuromuscular junction.

Mechanism:

Normally: nerve impulse → P/Q Ca²+ channels open → Ca²+ influx → synaptotagmin activated → vesicle fusion → ACh release
In Lambert-Eaton: IgG autoantibodies bind and destroy P/Q-type VGCCs → less Ca²+ enters → less ACh released → muscle weakness

Distinguishing feature from MG: In Lambert-Eaton, repeated stimulation temporarily INCREASES strength (because repetitive nerve firing gradually accumulates enough Ca²+ to release ACh) - the opposite of MG where repeated use worsens weakness.

Association: ~60% associated with Small Cell Lung Cancer (SCLC) - tumor cells express P/Q channels; antibodies cross-react with NMJ.

10. Myasthenia Gravis - Why Ocular Muscles First?

Ocular muscles are preferentially and earliest affected in MG for several reasons:

High firing rate: Extraocular muscles fire at very high frequencies (up to 200 Hz) to maintain precise eye movements. High-frequency firing rapidly depletes available ACh → "safety factor" exhausted quickly.
Low safety factor: The NMJ of extraocular muscles has a lower "safety factor" (ratio of ACh released to amount needed for activation) compared to limb muscles.
Small motor units: Each extraocular motor unit contains very few muscle fibers - tiny reduction in ACh causes noticeable weakness.
Different AChR subunit composition: Ocular muscle NMJs have a different isoform of AChR subunits compared to limb muscles, making them more vulnerable to antibody attack.
No fiber type diversity: They lack the redundancy of fast/slow fibers that limb muscles have.

Result: Ptosis and diplopia are the presenting features in ~50% of MG patients.

11. Choline Recycling

After ACh is released into the synapse:

Acetylcholinesterase (AChE) hydrolyzes ACh → choline + acetate
~50% of choline is actively recaptured by the presynaptic terminal via the high-affinity choline transporter (CHT1, also called hemicholinium-sensitive transporter)
Choline enters the terminal and is reused to synthesize new ACh via Choline Acetyltransferase (ChAT)

Hemicholinium-3 blocks this reuptake transporter → depletes ACh stores → neuromuscular blockade (used experimentally).

12. Rate-Limiting Step in ACh Synthesis

The rate-limiting step is choline uptake into the presynaptic terminal via the high-affinity choline transporter (CHT1).

Lippincott Pharmacology - "The uptake of choline is the rate-limiting step in ACh synthesis."

ACh synthesis pathway: Choline (from plasma/recycling) + Acetyl-CoA → [Choline Acetyltransferase (ChAT)] → Acetylcholine

Note: ChAT itself is not the rate-limiting enzyme - it is the availability of choline (transport into terminal) that limits the rate.

13. Saxitoxin Mechanism

Source: Produced by dinoflagellates (Alexandrium species) during red tides; accumulates in filter-feeding shellfish → Paralytic Shellfish Poisoning (PSP)

Mechanism: Saxitoxin binds to the outer vestibule of voltage-gated sodium channels (Site 1), physically occluding the channel pore. This is the same site as tetrodotoxin.

Blocks Na+ influx
No action potential generation
Flaccid paralysis, respiratory failure
Gating-independent - channel does not need to be open or closed; toxin binds and simply plugs the channel

14. Tetrodotoxin Mechanism

Source: Puffer fish (Fugu), blue-ringed octopus, some salamanders

Mechanism: Tetrodotoxin (TTX) also binds to Site 1 of voltage-gated sodium channels (same site as saxitoxin), blocking Na+ entry.

Binds from the extracellular side
Does not affect K+ or Ca²+ channels
Blocks action potential generation and propagation
Causes paresthesias, paralysis, respiratory arrest
No antidote - supportive care only

Key difference from Saxitoxin: Both block the same site - clinically similar, but TTX is found in puffer fish; STX in shellfish.

15. Cable Properties of Neurons

Neurons are not ideal electrical conductors. They behave like leaky cables - the lipid bilayer is an imperfect insulator, and axoplasm is a resistive medium.

Two key cable properties:

A. Length Constant (λ - lambda)

Distance over which a subthreshold voltage decays to 1/e (~37%) of its original value
Formula: λ = √(r_membrane / r_axoplasm)
Larger λ = signal travels further before decaying
Increased by: larger axon diameter, thick myelin (high membrane resistance)
Decreased by: leaky membranes, small diameter

B. Time Constant (τ - tau)

Time for membrane voltage to reach 63% of its final value in response to a current step
Formula: τ = R_m × C_m
Determines how quickly a neuron responds to input
Larger τ = slower response; smaller τ = faster response
Myelination reduces Cm → smaller τ → faster conduction

Significance for conduction:

Myelination dramatically increases λ (current jumps from node to node - saltatory conduction)
Large diameter + myelin = fastest conduction (Aα fibers, ~70-120 m/s)
Small unmyelinated axons = small λ, slow conduction (C fibers, ~0.5-2 m/s)

16. Why Is Conduction Slower in Diabetes?

In diabetic peripheral neuropathy, nerve conduction velocity (NCV) is reduced. Reasons:

Segmental demyelination: Chronic hyperglycemia damages Schwann cells → patchy demyelination → loss of saltatory conduction → slower NCV
Axonal atrophy: Axon diameter decreases → smaller length constant → slower conduction
Reduced Na+/K+-ATPase activity: Hyperglycemia inhibits Na+/K+ pump → resting membrane potential less negative → altered threshold and AP kinetics
Sorbitol accumulation: Aldose reductase converts glucose to sorbitol → osmotic stress → Schwann cell damage
Ischemia of vasa nervorum: Microvascular disease reduces blood supply to nerve → hypoxia damages myelin and axons

Earliest NCS findings: Reduced conduction velocity in sensory fibers (sural nerve), followed by motor fibers.

17. Tensilon Test (Edrophonium Test)

Edrophonium is a short-acting, reversible acetylcholinesterase inhibitor.

Used to diagnose: Myasthenia Gravis

Procedure:

Patient has ptosis or diplopia
IV edrophonium 2 mg given (test dose), then 8 mg
Within 30-60 seconds, if MG: dramatic improvement in ptosis/ocular movement
Effect lasts only ~5 minutes (hence "Tensilon" test - transient)

Mechanism: Edrophonium inhibits AChE → ACh accumulates in synapse → overcomes antibody-reduced AChR stimulation → muscle strength temporarily restored

Precautions: Can cause bradycardia/cardiac arrest - atropine must be at bedside. Has largely been replaced by antibody testing (anti-AChR, anti-MuSK) but still used acutely.

18. Ice Pack Test

Used to diagnose: Myasthenia Gravis (specifically for ptosis)

Procedure:

Apply a bag of ice wrapped in cloth to the closed eyelid for 2 minutes
If MG: ptosis improves after ice application

Mechanism:

AChE activity is temperature-dependent - it is inhibited by cold
Cooling the eyelid → reduced AChE activity → ACh persists longer in synapse → NMJ transmission improves → ptosis temporarily resolves

Advantage over Tensilon test: No risk of cardiac side effects; safe, non-invasive, can be done at bedside. Sensitivity ~80% for ocular MG.

19. Curare Mechanism

Curare (d-tubocurarine) is the classical neuromuscular blocker from South American arrow poison.

Mechanism: Competitive (non-depolarizing) antagonist at nicotinic acetylcholine receptors (nAChR) at the motor end plate

Binds to nAChR at the same site as ACh (α-subunits)
Does NOT activate the receptor (no depolarization)
Competes with ACh - the more curare present, the less ACh can bind
Result: No end-plate potential → no muscle contraction → flaccid paralysis

Reversal: By neostigmine (AChE inhibitor) - increases ACh concentration → outcompetes curare

Order of paralysis: Small muscles first (face, eyes) → limbs → diaphragm last (important clinically - respiratory paralysis requires ventilator support)

20. Subliminal Fringe

When a nerve impulse reaches a neuronal pool:

Discharge zone: Neurons that receive enough synaptic input to reach threshold and fire
Subliminal fringe: Neurons that receive subthreshold excitation - they are facilitated but don't fire

These "fringe" neurons are partially depolarized (brought closer to threshold) - they can be recruited if additional stimuli arrive.

Importance: The subliminal fringe is the anatomical basis for summation and facilitation - partially excited neurons can be pushed to threshold by a second input.

21. Summation

Two types:

A. Temporal Summation:

Same presynaptic neuron fires repeatedly in rapid succession
Each EPSP adds to the previous one before it decays
Cumulative depolarization reaches threshold → postsynaptic neuron fires
Requires high-frequency input

B. Spatial Summation:

Multiple presynaptic neurons fire simultaneously
Their individual EPSPs converge on the same postsynaptic neuron
Sum of all EPSPs reaches threshold
Requires convergence of inputs

Both types reflect integration of input at the postsynaptic membrane. Inhibitory postsynaptic potentials (IPSPs) can also summate to hyperpolarize the cell.

22. Facilitation

Facilitation occurs when a stimulus leaves a neuron (or neuronal pool) in an excited but subthreshold state - making it easier for a subsequent stimulus to trigger firing.

Mechanism: First stimulus partially depolarizes the membrane or partially activates signaling cascades → lowers the effective threshold for the next stimulus.

Post-tetanic potentiation: A burst of high-frequency stimulation leaves presynaptic terminals with elevated Ca²+ → subsequent single stimuli produce larger EPSPs (facilitation at presynaptic level).

Distinguished from summation: Summation is the arithmetic addition of potentials; facilitation is the change in excitability that makes the neuron more responsive.

23. Occlusion

Occlusion is the phenomenon where two inputs together produce a SMALLER combined response than expected from summation of their individual responses.

Mechanism: Two afferent inputs share overlapping neurons in their discharge zones. When both inputs fire simultaneously, these shared neurons can only fire once - they cannot fire more than once simultaneously. So the total output is less than the sum of separate outputs.

Contrast with facilitation: Facilitation occurs in the subliminal fringe (subthreshold neurons); occlusion occurs in the discharge zones (neurons that fire with either input alone).

Example: Two different nerve stimuli each excite neurons A, B, C and B, C, D respectively. Together they only produce A+B+C+D = 4, not 6 (A+B+C + B+C+D).

24. Fast vs Slow Axonal Transport

Feature	Fast Anterograde	Slow Transport	Fast Retrograde
Speed	200-400 mm/day	1-6 mm/day	200-300 mm/day
Motor protein	Kinesin	Kinesin (dynein?)	Dynein
Direction	Cell body → axon terminal	Cell body → terminal	Terminal → cell body
Cargo	Vesicles, membrane proteins, mitochondria, neurotransmitter precursors	Cytoskeletal proteins (tubulin, actin, neurofilaments), soluble enzymes	Used vesicle membranes, NGF, viruses (herpes, rabies, polio), toxins

Key points:

Kinesin moves toward (+) end of microtubules = anterograde (toward axon terminal)
Dynein moves toward (-) end = retrograde (toward cell body)
Retrograde transport is how trophic factors (NGF) signal back to the cell body
Rabies, herpes simplex, tetanus toxin all use retrograde fast transport to reach the CNS/spinal cord

25. Multiple Sclerosis Physiology

MS is an autoimmune demyelinating disease of the CNS (brain and spinal cord).

Pathophysiology:

Autoreactive T cells (Th1 and Th17) breach the blood-brain barrier
They target myelin basic protein (MBP) and other myelin antigens
Inflammatory cascade: T cells, activated macrophages, and B cells attack oligodendrocytes and myelin sheaths
Demyelinated plaques form, primarily in periventricular white matter, optic nerves, cerebellum, spinal cord
Saltatory conduction lost → continuous conduction attempted along demyelinated axon → dramatically slower or blocked conduction
Early: conduction may recover partially (remission) due to redistribution of Na+ channels along the bare axon, edema resolution, partial remyelination
Late: axonal degeneration occurs (permanent disability)

Physiological consequences of demyelination:

Slowed NCV
Conduction block (complete failure of transmission at demyelinated segment)
Uhthoff's phenomenon: Heat (exercise, fever) further slows conduction → temporary worsening
Lhermitte's sign: Neck flexion → "electric shock" down spine (demyelinated cervical cord is hypersensitive to mechanical distortion)

26. Guillain-Barré Syndrome (GBS) Physiology

GBS is an acute autoimmune peripheral demyelinating polyneuropathy (unlike MS which is CNS).

Pathophysiology:

Typically triggered 2-4 weeks after infection (commonly Campylobacter jejuni, CMV, EBV, influenza)
Molecular mimicry: Antibodies made against bacterial/viral antigens cross-react with gangliosides on peripheral nerve myelin (e.g., GM1, GD1a, GQ1b)
Antibody + complement attack Schwann cells → segmental demyelination of peripheral nerves
Starts distally, ascends proximally (ascending paralysis)
AMSAN variant: Axonal damage (worse prognosis)

NCS findings: Reduced conduction velocity, prolonged distal latencies, conduction block, temporal dispersion - all hallmarks of demyelination.

Autonomic involvement: Because autonomic ganglia also have gangliosides, autonomic dysfunction (arrhythmias, BP instability) can be life-threatening.

Recovery: Remyelination occurs over weeks to months. Most patients recover well, ~5% have permanent deficits.

27. Why Are Tendon Reflexes Absent in Peripheral Neuropathy?

The monosynaptic stretch reflex arc requires:

Intact Ia afferent fibers (from muscle spindle)
Intact synaptic connection in spinal cord
Intact motor efferent (Aα motor neuron axon)
Intact NMJ and muscle

In peripheral neuropathy, one or more links of this arc are damaged:

Sensory polyneuropathy: Ia fibers degenerate → no afferent signal reaches spinal cord
Motor neuropathy: Motor axon degenerated → no efferent signal reaches muscle
Demyelinating neuropathy: Slowed/blocked conduction in Ia or motor fibers → insufficient temporal synchrony for reflex

Tendon reflexes are lost early in peripheral neuropathy (especially ankle jerks in length-dependent polyneuropathy) because sensory fibers (particularly large myelinated Ia and Aβ fibers) are often damaged first. Their loss breaks the reflex arc.

This is in contrast to upper motor neuron lesions (spinal cord/brain) where reflexes are exaggerated (hyperreflexia) because the descending inhibitory pathways are lost.

28. Diseases Affecting Myelin

Central Nervous System (CNS) - Oligodendrocytes make myelin:

Disease	Type	Key Feature
Multiple Sclerosis	Autoimmune demyelination	Periventricular plaques, relapsing-remitting
Progressive Multifocal Leukoencephalopathy (PML)	JC virus infection of oligodendrocytes	Immunocompromised patients
Metachromatic Leukodystrophy	Arylsulfatase A deficiency → sulfatide accumulation	Metachromatic staining
Krabbe Disease	Galactocerebrosidase deficiency → psychosine	Globoid cells
Adrenoleukodystrophy (ALD)	ABCD1 mutation → VLCFA accumulation	X-linked, "Lorenzo's Oil"
CNS Pelizaeus-Merzbacher	PLP1 gene mutation	Congenital dysmyelination

Peripheral Nervous System (PNS) - Schwann cells make myelin:

Disease	Type	Key Feature
Guillain-Barré Syndrome	Autoimmune	Acute ascending paralysis, post-infectious
Charcot-Marie-Tooth (CMT)	Hereditary	PMP22 duplication (type 1A) - most common
CIDP	Chronic autoimmune	Chronic relapsing demyelinating polyneuropathy
Diphtheria	Bacterial toxin	Demyelinates cranial and peripheral nerves

29. Goldman Equation vs Nernst Equation

Feature	Nernst Equation	Goldman Equation
Purpose	Equilibrium potential for a single ion	Resting membrane potential considering multiple ions
Formula	E_ion = (RT/zF) × ln([ion]_out / [ion]_in)	V_m = (RT/F) × ln[(P_K[K⁺]o + P_Na[Na⁺]o + P_Cl[Cl⁻]i) / (P_K[K⁺]i + P_Na[Na⁺]i + P_Cl[Cl⁻]o)]
Ions considered	One at a time (e.g., just K+)	K+, Na+, Cl- (multiple simultaneously)
Permeability	Assumes only one ion is permeable	Weighs contribution of each ion by its relative permeability (P)
Gives	Equilibrium potential (E_K = -90 mV; E_Na = +60 mV)	Actual resting membrane potential (~-70 mV)
Limitations	Doesn't account for multiple permeabilities	Doesn't account for electrogenic pumps

Key insight: The Goldman equation is essentially a weighted average of Nernst potentials, weighted by the permeability to each ion. At rest, P_K >> P_Na → resting potential is close to E_K (~-90 mV) but not exactly (-70 mV), because some Na+ permeability pulls it positive.

Summary Quick-Reference Table

Topic	Key Point
Hodgkin cycle	Positive feedback: depolarization → Na+ influx → more depolarization
Synaptobrevin	v-SNARE (VAMP) on vesicle membrane
Syntaxin	t-SNARE on plasma membrane
Synaptotagmin	Ca²+ sensor that triggers final fusion
Temporal dispersion	Wider, lower CAP due to different fiber speeds; sign of demyelination
Botulinum + dry mouth	Blocks ACh at parasympathetic salivary gland synapses
Botulinum SNARE target	Type A/E → SNAP-25; Type B → Synaptobrevin
Neuropraxia	Conduction block only; full recovery
Axonotmesis	Axon cut but tube intact; good recovery
Neurotmesis	Complete disruption; poor recovery
Opisthotonus	Tetanus/strychnine → loss of inhibitory interneurons → extensor spasm
Lambert-Eaton	P/Q-type VGCCs attacked; repetitive stimulation improves strength
MG ocular muscles first	High firing rate, low safety factor at extraocular NMJ
ACh rate-limiting step	Choline uptake (not ChAT enzyme)
Saxitoxin & TTX	Both block voltage-gated Na+ channel Site 1; puffer fish = TTX; shellfish = STX
Cable properties	λ (length constant), τ (time constant); myelin increases λ → saltatory conduction
Diabetes slow conduction	Schwann cell damage, demyelination, sorbitol, ischemia
Tensilon test	Edrophonium → AChE inhibitor → diagnoses MG
Ice pack test	Cold inhibits AChE → ptosis improves → MG diagnosis
Curare	Competitive nAChR antagonist at NMJ → flaccid paralysis
Subliminal fringe	Neurons excited but below threshold; basis for facilitation
Temporal summation	Same neuron fires rapidly; EPSPs add up
Spatial summation	Multiple inputs converge; EPSPs add up
Facilitation	Subthreshold priming makes next stimulus more effective
Occlusion	Shared neurons fire only once → total < expected sum
Fast anterograde transport	Kinesin, 200-400 mm/day; vesicles, mitochondria
Slow axonal transport	1-6 mm/day; cytoskeletal proteins
Fast retrograde transport	Dynein; NGF, viruses, toxins back to cell body
MS physiology	CNS autoimmune demyelination; oligodendrocytes attacked
GBS physiology	PNS autoimmune demyelination; ascending paralysis post-infection
Absent reflexes in neuropathy	Ia afferent or motor efferent fiber damage breaks reflex arc
Nernst equation	Single ion equilibrium potential
Goldman equation	Multi-ion resting membrane potential (weighted by permeability)

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