Neurophysiology & Neurotransmitters

Resting potential and the action potential

Resting membrane potential. About -70 mV. At rest the membrane is most permeable to K⁺ through leak channels, so K⁺ diffusing out pulls the potential toward the K⁺ equilibrium potential (about -90 mV). The Na⁺/K⁺-ATPase pumps 3 Na⁺ out and 2 K⁺ in, maintaining high intracellular K⁺ and high extracellular Na⁺; because it moves more positive charge out than in, it adds slightly to the negativity.

Resting potential tracks K⁺, so a rise in extracellular K⁺ (hyperkalemia) depolarizes excitable cells.

The action potential. When depolarization reaches threshold (about -55 mV), voltage-gated Na⁺ channels open and rapid Na⁺ influx drives the upstroke. Na⁺ channels then inactivate while voltage-gated K⁺ channels open, and K⁺ efflux repolarizes the membrane. Because K⁺ channels close slowly, a brief hyperpolarization (undershoot) follows. Action potentials are all-or-none and do not summate; stimulus strength is encoded by firing frequency.

Refractory periods. In the absolute refractory period, voltage-gated Na⁺ channels are inactivated, so no stimulus can trigger a new action potential; this ensures one-way propagation. In the relative refractory period, some Na⁺ channels have reset but K⁺ still flows out and the membrane is hyperpolarized, so a larger-than-normal stimulus is required.

Channel blockers. Local anesthetics such as lidocaine, and the pufferfish toxin tetrodotoxin, block voltage-gated Na⁺ channels and prevent action potentials.

Conduction and myelin

Saltatory conduction. Myelin insulates the axon, so action potentials regenerate only at the nodes of Ranvier, which are dense in voltage-gated Na⁺ channels. Current jumps from node to node, greatly increasing velocity. Larger-diameter and more heavily myelinated axons conduct fastest.

Demyelination. Loss of myelin slows or blocks saltatory conduction: in the CNS in multiple sclerosis, and in the PNS in Guillain-Barré syndrome.

Synaptic transmission

Calcium triggers release. When the action potential reaches the axon terminal, it opens voltage-gated Ca²⁺ channels. Ca²⁺ influx triggers SNARE-mediated fusion of neurotransmitter vesicles with the membrane and exocytosis into the cleft. The transmitter binds postsynaptic receptors, and signaling ends by reuptake (e.g., monoamine transporters), enzymatic degradation (e.g., acetylcholinesterase), or diffusion.

Toxins and antibodies at the synapse. Botulinum and tetanus toxins cleave SNARE proteins, blocking vesicle fusion and transmitter release. Botulinum acts at the neuromuscular junction and causes flaccid paralysis. Antibodies against presynaptic voltage-gated Ca²⁺ channels (Lambert-Eaton syndrome) reduce ACh release and cause weakness.

Excitatory and inhibitory signaling

Glutamate. The main excitatory CNS transmitter, acting on ionotropic NMDA and AMPA receptors. Excess glutamate causes excitotoxic neuronal injury, the target of the NMDA antagonist memantine.

GABA. The main inhibitory CNS transmitter. GABA-A is an ionotropic chloride channel whose opening hyperpolarizes the neuron; it is the target of benzodiazepines, barbiturates, and alcohol. GABA-B is metabotropic and opens K⁺ channels.

Glycine. The main inhibitory transmitter in the spinal cord.

Tetanus toxin travels retrogradely into the cord and blocks glycine/GABA release from Renshaw inhibitory interneurons, causing spastic paralysis.

Neurotransmitter nuclei and the chemistry of disease

Every transmitter has an address. These nuclei are altered in disease and by drugs of abuse.

Parkinson disease. Substantia nigra loss lowers dopamine and leaves acetylcholine relatively high; serotonin is also decreased. This dopamine/ACh imbalance is the rationale for both dopaminergic therapy and antimuscarinics such as benztropine, which help tremor.

Huntington disease. Caudate degeneration lowers GABA and acetylcholine while dopamine is relatively increased, producing chorea: the neurochemical mirror image of Parkinson disease. Dopamine-depleting (tetrabenazine) or dopamine-blocking drugs reduce chorea.

Huntington = too much dopamine relative to GABA; Parkinson = too little dopamine. Opposite chemistries, opposite movement disorders.

Alzheimer disease. Acetylcholine falls, largely from degeneration of the basal nucleus of Meynert, so cholinesterase inhibitors (donepezil, rivastigmine, galantamine) are used symptomatically; memantine targets glutamate excitotoxicity.

Psychiatric disease. Depression is linked to decreased norepinephrine, serotonin, and dopamine (the monoamine hypothesis). Anxiety shows increased norepinephrine with decreased GABA and serotonin. Schizophrenia shows increased dopaminergic activity in the mesolimbic pathway (positive symptoms), with NMDA/glutamate hypofunction implicated.