Neural Physiology: Dendrites, Synapses, and Neurotransmission

Functional Anatomy and Physiology of Dendrites

• Dendritic Structure: Dendrites are extensions that are spaced in all directions around the neuronal soma (cell body). They are designed to receive signals (neurotransmitters) from a vast array of presynaptic neurons.

• Signal Integration: The structure of dendrites allows for the summation of signals. Many presynaptic terminals can be stimulated simultaneously, and their effects are integrated at the soma and axon hillock.

• Signal Transmission via Graded Potentials: Dendrites transmit signals through graded local potentials rather than action potentials. These potentials are generated by the opening of ligand-gated channels (LGCs).

• Ligand-Gated Channels (LGCs):     * LGCs function as neurotransmitter receptors.     * They are primarily located on the dendrites and the cell body.     * The intensity of the generated potential diffuses (decreases) as it moves away from the initial site of stimulus.

The Excitatory Postsynaptic Potential (EPSP)

• Definition: An EPSP is an increase in voltage above the normal resting membrane potential. This shift toward a less negative value (depolarization) makes the neuron more likely to reach the threshold for an action potential.

• Magnitude and Threshold:     * A single EPSP typically measures between $0.5-1.0\,mV$.     * To reach the firing threshold, a voltage difference of approximately $10-20\,mV$ is often required.

• Ionic Mechanism (Na+/K+ Permeability): To generate a depolarizing event, the membrane must become more permeable to sodium ($Na^+$) or less permeable to potassium ($K^+$).

• Standard Ion Concentrations:     * Axon Interior:         * $Na^+$: $14\,mEq/L$         * $K^+$: $120\,mEq/L$         * $Cl^-$: $8\,mEq/L$     * Extracellular Fluid:         * $Na^+$: $142\,mEq/L$         * $K^+$: $4.5\,mEq/L$         * $Cl^-$: $107\,mEq/L$

• Excitatory Neurotransmitters: These are substances that create depolarizing events. It is important to note that the receptor itself determines the excitatory nature of the response.

The Inhibitory Postsynaptic Potential (IPSP)

• Definition: Inhibitory neurotransmitters cause hyperpolarization, making the membrane potential more negative than the resting potential. This makes the neuron less likely to reach the threshold.

• Ionic Mechanisms:     * Potassium ($K^+$) Movement: Opening $K^+$ channels allows positively charged ions to move to the exterior, increasing negativity inside.     * Chloride ($Cl^-$) Movement: Opening $Cl^-$ channels allows negatively charged ions to move into the interior, also increasing negativity.

• Voltage Example: A hyperpolarized neuron might reach a membrane potential of approximately $-90\,mV$ (compared to a depolarized state of $-45\,mV$ or a resting state).

Summation and Neural Integration

• The Decision to Respond: Whether a neuron fires an action potential depends on the temporal and spatial summation of all incoming EPSPs and IPSPs.

• Temporal Summation: This occurs when a single presynaptic neuron fires repeatedly in rapid succession, "adding up" the potentials over time.

• Spatial Summation: This occurs when multiple different presynaptic neurons fire simultaneously at different locations on the postsynaptic neuron.

• Kinetics of Potentials:     * Action potentials take approximately $1\,msec$.     * Graded potentials (EPSPs/IPSPs) can last approximately $15\,msec$.     * Because graded potentials last longer than action potentials, they provide a window for the "adding" effect of multiple stimuli.

• Rapid Control: LG channels open and close rapidly, allowing for the quick activation or inhibition of postsynaptic neurons.

Ion Channel Dynamics and Refractory Periods

• Gating States of Sodium ($Na^+$) VGCs: Depolarization triggers three stages:     1. Activation: The channel opens to allow ion flow.     2. Inactivation: The channel closes immediately after activation (non-conducting state).     3. Deactivation: The channel returns to its resting closed state.

• Potassium ($K^+$) Channels: Unlike sodium channels, most potassium channels show activation and deactivation but typically do not exhibit inactivation.

• Absolute Refractory Period: During this time, $Na^+$ VGCs cannot be stimulated to open again because they are either already open or in the inactivated state.

• Relative Refractory Period: During this time, $Na^+$ VGCs can open if enough channels have reset (deactivated). This requires a stimulus stronger than normal, especially if the membrane potential is still more negative than the resting membrane potential (RMP).

Functions and Conduction of Action Potentials

• Information Delivery to the CNS:     * Sensory Encoding: Information is encoded by the frequency of action potentials, as the amplitude of an AP cannot change (all-or-none principle).

• Transmission Speed Factors:     * Fiber size (diameter).     * Myelination status.

• Saltatory Conduction:     * Action potentials occur only at the Nodes of Ranvier, where sodium channels are highly concentrated.     * The signal "jumps" from node to node.     * Benefits: Increased velocity and energy conservation.

• Non-nervous Tissue: In tissues like muscle, APs serve as initiators for cellular responses, such as muscle contraction.

Multiple Sclerosis (MS)

• Pathophysiology: MS is an immune-mediated inflammatory demyelinating disease of the Central Nervous System (CNS).

• Epidemiology:     * Prevalence: Approximately $1$ per $1000$ people in the United States.     * Gender Ratio: Female-to-male ratio is $2:1$.     * Highest Incidence: Whites of Northern European descent.

• Clinical Presentation:     * Symptoms are often difficult for patients to describe and may include paresthesia (numbness/tingling) of a hand or weakness in a leg.     * Visual disturbances (loss of vision) are common.     * Early symptoms often resolve spontaneously, leading to a delay in seeking medical attention. Eventually, neurologic deficits become frequent or incomplete in their resolution.

Synaptic Transmission Mechanics

• Presynaptic Components:     * Synaptic Vesicles: Store the neurotransmitter.     * Mitochondria: Provide the energy required to synthesize neurotransmitters.     * Voltage-Gated Calcium Channels: Crucial for triggering release.

• The Transmission Process:     1. An action potential depolarizes the presynaptic membrane.     2. Voltage-operated calcium channels (VOCCs) open, allowing an influx of $Ca^{2+}$.     3. $Ca^{2+}$ induces the release of neurotransmitters (NTS) into the synaptic cleft.     4. NTS diffuses across the cleft and reversibly binds to LGC receptors on the postsynaptic membrane.     5. Gates open, allowing ion diffusion (resulting in an EPSP or IPSP).

• NTS Removal: Neurotransmitters must be removed to terminate the signal via destruction (enzymatic), diffusion away from the cleft, or reuptake into the presynaptic terminal.

Major Neurotransmitter Systems

• Acetylcholine (ACh):     * Used in Neuromuscular Junctions (NMJs).     * Sympathetic PNS: Used by pre-ganglionic neurons only.     * Parasympathetic PNS: Used by both pre- and post-ganglionic neurons.     * Enzymes: Choline acetyltransferase (ChAT) forms ACh; Acetylcholinesterase (AChE) removes it from the synapse.

• Catecholamines (Norepinephrine, etc.):     * Derived from the amino acid tyrosine.     * Removed by reuptake via sodium-dependent transporters or glial cell absorption.     * Norepinephrine: Can be excitatory or inhibitory depending on the receptor.     * Degradation: Mono-amine oxidase (MAO) degrades catecholamines.     * Clinical Note: MAO-inhibitors are used as anti-anxiety agents; they should not be mixed with sympathomimetics.

• Serotonin (5-HT):     * Synthesized from tryptophan.     * Functions as a mood elevator and "feel-good" neurotransmitter; involved in sleep and mood regulation.     * Clinical/Drugs: SSRIs (Selective Serotonin Reuptake Inhibitors) are antidepressants. Ecstasy potentiates effects, while LSD blocks its activity.

• GABA (Gamma-Aminobutyric Acid):     * Major inhibitory neurotransmitter in the CNS.     * Deficiency: Decreased GABA is linked to seizures.     * Agonists: Valium, benzodiazepines, and ethanol trigger GABA receptors. Benzodiazepines are utilized during ethanol detox.

• Glutamate:     * Most abundant neurotransmitter in the CNS; used by nearly all excitatory neurons.     * Opens $Na^+$ and $Ca^{2+}$ channels.     * Pathology: Excitotoxicity occurs with unregulated calcium influx (unregulated apoptosis/cell suicide).     * Ketamine: An anesthetic and club drug (“Special K”) that blocks glutamate receptors; it shows promise as a rapid antidepressant for suicidal patients.

Clinical Correlation: Phenylketonuria (PKU)

• Nature of Disorder: Genetic, autosomal recessive disorder ($1:20,000$ births).

• Cause: Lack of the enzyme phenylalanine hydroxylase, preventing the conversion of phenylalanine to tyrosine.

• Pathology: Phenylalanine is converted into toxic breakdown products which accumulate and lead to neuronal degeneration, seizures, poor motor development, and irreversible mental retardation.

• Management:     * Newborn screening (heel stick blood sample) is mandatory in many states (including CA).     1. Prevented by dietary restriction of phenylalanine (no whole protein; use specialized amino acid sources).     2. Restriction is vital during the development of the nervous system (at least through adulthood).

• Maternal PKU: A mother with the disease can cause toxin build-up on the developing baby's neurons.

Pharmacology and Toxicology of Neurotransmission

• Type of Paralysis:     * Spastic Paralysis: Continuous, uncoordinated contraction.     * Flaccid Paralysis: Complete lack of muscle tone; no mechanical result.

• Sodium VGC Blockers (Result: Flaccid Paralysis):     * Lidocaine: Used as local anesthesia.     * Tetrodotoxin (TTX): Found in puffer fish and newts.     * Saxitoxin (SXT): Produced by dinoflagellates in "red tide"; accumulates in shellfish.

• Vesicle Blockers (Result: Flaccid Paralysis):     * Clostridium botulinum: A protease that breaks down fusion/docking proteins, preventing neurotransmitter release (BOTOX).

• Muscarinic ACh-R (mACh-R) Blockers:     * Atropine ("Belladonna"): Competitor that blocks ACh receptors. Prevents pupil constriction (causes dilation). Affects smooth muscle, heart, and glands.

• Acetylcholinesterase (AChE) Inhibitors:     * Reversible Inhibitors: Neostigmine, Pyridostigmine, Physiostigmine, Edrophonium. Used for Myasthenia Gravis (to treat ptosis). Cause spastic paralysis.     * Irreversible Inhibitors: DFP (di-isopropyl fluorophosphates) and Sarin (chemical warfare). Cause spastic paralysis.     * Overdose Treatment: Injected Atropine (to block mAChR) and Protopam (to compete for the inhibitors).