1.1 Nervous System Structure, Neurons & Synaptic Transmission

1.1 Nervous System Structure, Neurons & Synaptic Transmission

The human nervous system is a highly complex electro-chemical communication network that senses internal and external environments, integrates information, and coordinates motor, autonomic, and cognitive responses. For the MCAT, mastering the nervous system requires an integrated understanding of anatomical divisions, cellular components, action potential electrophysiology, and synaptic mechanics.

Functional & Anatomical Divisions of the Nervous System

Anatomically, the nervous system is partitioned into the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). The CNS consists of the brain and spinal cord, serving as the primary site of information processing, integration, and command generation. The PNS encompasses all neural structures outside the CNS, including 12 pairs of cranial nerves and 31 pairs of spinal nerves, which connect the CNS to limbs, organs, and peripheral tissues.

Functionally, neural pathways in the PNS are divided into two main pathways:

1. Sensory (Afferent) Neurons: Carry sensory input from peripheral receptors toward the CNS.
2. Motor (Efferent) Neurons: Carry motor commands away from the CNS to peripheral effectors (muscles and glands).

A useful high-yield MCAT mnemonic is SAME DAME: Sensory = Afferent, Motor = Efferent; Dorsal = Afferent, Ventral = Efferent (in the spinal cord, sensory afferents enter via the dorsal root, whereas motor efferents exit via the ventral root).

The motor (efferent) division of the PNS is further divided into the Somatic Nervous System and the Autonomic Nervous System (ANS):

• Somatic Nervous System: Governs voluntary control of skeletal muscle contraction. It features a direct, single-neuron pathway: a single motor neuron extends its axon from the CNS directly to the skeletal muscle target, releasing acetylcholine (ACh) onto nicotinic acetylcholine receptors at the neuromuscular junction.
• Autonomic Nervous System (ANS): Governs involuntary control of cardiac muscle, smooth muscle, and glandular secretion. Unlike the somatic system, the ANS utilizes a two-neuron relay pathway comprising a preganglionic neuron (cell body in CNS) and a postganglionic neuron (cell body in an autonomic ganglion in the PNS).

The ANS is subdivided into two opposing branches: the Sympathetic Nervous System (SNS) and the Parasympathetic Nervous System (PNS).

Neuronal Microstructure & Glial Support Cells

Neurons are the principal signal-conducting cells of the nervous system. A prototypical multipolar neuron consists of four structural domains:

1. Dendrites: Branched extensions that receive synaptic inputs from other neurons and convey graded potentials toward the soma.
2. Soma (Cell Body): Contains the nucleus, mitochondria, Golgi apparatus, and dense rough endoplasmic reticulum known as Nissl bodies, responsible for protein synthesis.
3. Axon Hillock: The funnel-shaped junction between the soma and axon. It has a high density of voltage-gated sodium channels and acts as the trigger zone where spatial and temporal inputs are integrated to determine if the threshold for an action potential (-55 mV) is met.
4. Axon & Axon Terminals: Long cylindrical projection that propagates action potentials over distances. The terminal bouton contains synaptic vesicles packed with neurotransmitters.

Neurons are supported, insulated, and nourished by glial cells (neuroglia), which outnumber neurons in the brain:

Electrophysiology of Resting Potential & the Action Potential

Neurons transmit signals via electrical impulses called action potentials. In the resting state, neurons maintain an asymmetric charge distribution across the plasma membrane called the resting membrane potential ((V_m)), typically around (-70\text{ mV}) inside relative to outside.

Maintenance of Resting Potential

1. (Na^+/K^+) ATPase (Sodium-Potassium Pump): Actively transports (3\text{ Na}^+) ions out of the cell for every (2\text{ K}^+) ions brought in, consuming 1 ATP molecule. This pump is electrogenic, generating a net (-1) charge movement per cycle and establishing steep concentration gradients (([\text{Na}^+]{\text{out}} \approx 145\text{ mM}), ([\text{Na}^+]{\text{in}} \approx 12\text{ mM}); ([\text{K}^+]{\text{in}} \approx 140\text{ mM}), ([\text{K}^+]{\text{out}} \approx 4\text{ mM})).
2. Passive Leak Channels: Resting neuronal membranes have significantly higher permeability to (\text{K}^+) than to (\text{Na}^+) due to abundant non-gated (\text{K}^+) leak channels. As (\text{K}^+) diffuses down its concentration gradient out of the cell, negative intracellular proteins are left behind, driving the membrane potential negative toward the potassium equilibrium potential ((E_{\text{K}^+})).

The theoretical equilibrium potential for a single ion is calculated using the Nernst Equation: [ E_{\text{ion}} = \frac{RT}{zF} \ln\left(\frac{[\text{Ion}]{\text{outside}}}{[\text{Ion}]{\text{inside}}}\right) = \frac{61.5}{z} \log_{10}\left(\frac{[\text{Ion}]{\text{outside}}}{[\text{Ion}]{\text{inside}}}\right) \quad (\text{at } 37^\circ\text{C}) ] For (\text{K}^+), (E_{\text{K}^+} \approx -90\text{ mV}). For (\text{Na}^+), (E_{\text{Na}^+} \approx +60\text{ mV}). Because resting potassium permeability is much higher than sodium permeability, resting (V_m) ((-70\text{ mV})) lies much closer to (E_{\text{K}^+}).

Phases of the Action Potential

1. Resting State: (V_m = -70\text{ mV}). Voltage-gated channels are closed.
2. Threshold Stimulus: Incoming postsynaptic potentials summate at the axon hillock. If depolarizations raise (V_m) to threshold ((\approx -55\text{ mV})), an all-or-none action potential is triggered.
3. Depolarization Phase: Reaching threshold causes rapid opening of voltage-gated (\text{Na}^+) channels. (\text{Na}^+) rushes into the axon down both its chemical concentration gradient and electrical gradient (positive feedback loop), causing (V_m) to depolarize rapidly toward (\approx +35\text{ mV}).
4. Peak & Repolarization Phase: At (\approx +35\text{ mV}), two critical events occur simultaneously:
   • Voltage-gated (\text{Na}^+) channels close their inactivation gates (entering a refractory, inactivated state).
   • Voltage-gated (\text{K}^+) channels open (delayed rectifier channels). (\text{K}^+) rapidly exits the cell down its electrochemical gradient, causing repolarization back toward negative voltages.
5. Hyperpolarization (Undershoot): Voltage-gated (\text{K}^+) channels close slowly, permitting continued (\text{K}^+) efflux that temporarily drives (V_m) past (-70\text{ mV}) toward (-90\text{ mV}) ((E_{\text{K}^+})).
6. Restoration: The (\text{Na}^+/\text{K}^+) ATPase pump and leak channels restore the resting ionic concentrations and membrane potential.

Refractory Periods & Conduction Velocity

• Absolute Refractory Period: Spans depolarization and early repolarization. Voltage-gated (\text{Na}^+) channels are inactivated. No stimulus, regardless of strength, can initiate a second action potential. This enforces unidirectional propagation along the axon and sets an upper limit on maximum firing frequency.
• Relative Refractory Period: Corresponds to the hyperpolarization phase. (\text{Na}^+) channels have reset to their closed/de-inactivated state, but (V_m) is hyperpolarized and (\text{K}^+) channels remain open. A second action potential can be generated, but requires a significantly larger (suprathreshold) depolarizing stimulus.

Conduction velocity depends on two axonal parameters:

1. Axon Diameter: Larger diameter decreases internal cytoplasmic resistance ((R_{\text{in}})), increasing conduction speed.
2. Myelination: Myelin acts as an electrical insulator, increasing membrane resistance ((R_m)) and reducing membrane capacitance ((C_m)). Action potentials cannot occur under myelin sheaths; instead, ionic current flows passively and rapidly down the axon interior between non-myelinated gaps called Nodes of Ranvier. Voltage-gated (\text{Na}^+) channels concentrated at these nodes regenerate the action potential, a rapid process known as saltatory conduction.

Chemical Synapses & Signal Transduction

When an action potential reaches the axon terminal, electrical signaling is converted into chemical signaling at the synaptic cleft:

1. Calcium Influx: Action potential depolarization opens voltage-gated (\text{Ca}^{2+}) channels in the presynaptic terminal membrane.

2. Vesicle Exocytosis: (\text{Ca}^{2+}) rushes into the terminal down its concentration gradient and binds to synaptotagmin, triggering SNARE proteins to fuse neurotransmitter-filled synaptic vesicles with the presynaptic membrane, releasing neurotransmitter into the cleft.

3. Receptor Binding: Neurotransmitters diffuse across the (\approx 20\text{ nm}) cleft and bind specifically to receptors on the postsynaptic membrane:

   • Ionotropic Receptors (Ligand-Gated Ion Channels): Direct, rapid responses. Binding opens or closes an ion channel directly (e.g., Nicotinic ACh receptors).
   • Metabotropic Receptors (G-Protein Coupled Receptors - GPCRs): Indirect, slower, long-lasting responses. Binding activates intracellular G-protein cascades, generating second messengers (e.g., cAMP, (\text{IP}_3/\text{DAG})) that modulate ion channels or gene transcription (e.g., Muscarinic ACh receptors).

4. Postsynaptic Potentials:

   • Excitatory Postsynaptic Potential (EPSP): Influx of cations (e.g., (\text{Na}^+) or (\text{Ca}^{2+})) causes local depolarization, bringing (V_m) closer to threshold.
   • Inhibitory Postsynaptic Potential (IPSP): Influx of anions (e.g., (\text{Cl}^-)) or efflux of cations ((\text{K}^+)) causes local hyperpolarization, moving (V_m) further from threshold.
   • Integration (Summation): Temporal summation combines multiple high-frequency signals from a single presynaptic terminal over time. Spatial summation combines simultaneous signals from multiple distinct presynaptic terminals across the dendritic tree.

5. Signal Termination: Neurotransmitters must be cleared rapidly to prevent continuous receptor activation. Termination occurs via three primary mechanisms:

   • Enzymatic Degradation: Breakdown by specific enzymes (e.g., Acetylcholinesterase breaks down ACh into choline and acetate).
   • Presynaptic Reuptake: Active transport back into the presynaptic terminal via specialized transporter proteins (e.g., Serotonin transporter SERT, Dopamine transporter DAT).
   • Astrocytic Uptake & Diffusion: Surrounding astrocytes absorb neurotransmitters (e.g., Glutamate) or the transmitter diffuses away out of the cleft.

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The Reflex Arc: Behavior Produced Below the Brain

The AAMC names the reflex arc as the model neural circuit because it demonstrates that a complete stimulus-to-response behavior can be generated by the spinal cord before the brain is ever informed.

Canonical sequence: receptor → sensory (afferent) neuron → dorsal root → spinal integration center (with or without interneurons) → motor (efferent) neuron → effector muscle.

Two implications the exam tests directly:

1. Speed comes from bypassing the cortex. You withdraw your hand and then consciously feel the pain, because the motor output is organized segmentally while the ascending nociceptive signal is still traveling to the thalamus and cortex.
2. Reflexes localize lesions. An absent or diminished reflex implicates the peripheral arc itself (dorsal root, sensory neuron, motor neuron, or muscle), whereas a hyperactive reflex implicates loss of descending inhibition from the brain — the classic upper motor neuron sign. Reflex testing is therefore a bedside probe of exactly the circuit diagrammed above.