CNS Neuroanatomy 6

Synaptic transmission steps

Sequence: action potential arrives → voltage-gated Ca2+ channels open → Ca2+ triggers vesicle docking and neurotransmitter release → neurotransmitter diffuses and binds receptor → postsynaptic response → neurotransmitter degraded, reuptaken, or diffuses away.

Ionotropic receptor definition

Ligand-gated receptor that is also an ion channel; produces fast changes in membrane potential and closes when neurotransmitter leaves.

Metabotropic receptor definition

G protein coupled receptor that acts via second messengers; slower onset, signal amplification, and longer-lasting effects.

Presynaptic Ca2+ role in exocytosis

Voltage-gated Ca2+ entry into the axon terminal is the trigger for synaptic vesicle docking and neurotransmitter release.

Neurotransmitter clearance mechanisms

Enzymatic degradation in cleft, transporter-mediated reuptake into presynaptic terminal or glia, and diffusion out of the cleft.

Drug targets at synapse

Key drug targets include voltage-gated Ca2+ channels (release), enzymes that degrade transmitters, and reuptake transporters.

Acetylcholine synthesis

Acetyl-CoA + choline → acetylcholine catalyzed by choline acetyltransferase (CAT) in axon terminal.

Acetylcholine degradation

Acetylcholinesterase in the synaptic cleft hydrolyzes ACh to acetate and choline; choline is reuptaken into the terminal.

Cholinergic receptors types

Nicotinic ionotropic receptors mediate fast depolarization; muscarinic metabotropic receptors modulate slower, varied intracellular responses.

Cholinergic functions in CNS

ACh from basal forebrain projections supports attention, learning, memory, cognition and modulates reward and anxiety pathways.

Alzheimer disease cholinergic link

Degeneration of basal forebrain cholinergic neurons and their cortical/hippocampal projections contributes to memory loss and cognitive decline.

Myasthenia gravis pathophysiology

Autoantibodies target nicotinic ACh receptors at the motor endplate leading to fewer receptors, reduced depolarization, and muscle weakness; AChE inhibitors prolong ACh in cleft.

Catecholamine synthesis pathway

Tyrosine → L-DOPA (tyrosine hydroxylase) → dopamine (aromatic L-amino acid decarboxylase) → norepinephrine (dopamine β-hydroxylase) → epinephrine (phenylethanolamine N-methyltransferase).

Catecholamine degradation enzymes

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) metabolize catecholamines; MAO has A and B isoforms with substrate selectivity.

Dopaminergic system roles

Dopamine modulates movement, reward, motivation, attention, and mood; loss in basal ganglia causes Parkinsonism, excess linked to psychosis.

Adrenergic receptor types and signaling(Adrenergic α and β receptors are metabotropic GPCRs that mediate sympathetic effects and central noradrenergic modulation of arousal and mood.)

NOTE: receptor subtypes produce diverse second messenger responses.

Serotonin synthesis and termination

Tryptophan → 5-hydroxytryptophan (tryptophan hydroxylase) → 5-HT (aromatic L-amino acid decarboxylase); action terminated by SERT reuptake and degradation by MAO.

Serotonin central functions

5-HT regulates mood, anxiety, sleep-wake cycles, pain modulation, and many sensory/motor processes; SSRIs block SERT to increase synaptic 5-HT.

Glutamate role in CNS

Glutamate is the principal excitatory neurotransmitter in the brain and is central to synaptic plasticity and long-term potentiation.

Ionotropic glutamate receptor subtypes

AMPA and kainate receptors are Na+ permeable and mediate fast excitatory transmission; NMDA receptors are Ca2+ permeable and gated by voltage-dependent Mg2+ block.

NMDA receptor unique properties(NMDA receptors require glutamate and co-agonist glycine, are blocked by Mg2+ at rest, allow Ca2+ influx that mediates synaptic plasticity and can trigger excitotoxicity if overactivated.)

Pharmacologic antagonists include memantine and PCP.

Glutamate excitotoxicity concept

Excessive glutamate receptor activation causes massive Ca2+ influx, triggering cell death pathways and contributing to stroke and neurodegenerative injury.

GABA overview

GABA is the main inhibitory neurotransmitter in the brain; it reduces neuronal circuit activity through GABAA ionotropic Cl- channels and GABAB metabotropic receptors.

GABAA receptor pharmacology

GABAA is a Cl- channel that is modulated by benzodiazepines, barbiturates, alcohol, propofol, volatile anesthetics and neurosteroids to enhance inhibition.

GABA synthesis and catabolism

Glutamate is converted to GABA by glutamic acid decarboxylase (GAD); GABA is metabolized by GABA transaminase.

Glycine neurotransmitter role

Glycine is the main inhibitory transmitter in spinal cord and brainstem via its own Cl- receptor and acts as an essential NMDA co-agonist in forebrain.

Glycine transporters and therapeutic target

GlyT1 on glia and GlyT2 on terminals control glycine levels; GlyT1 inhibitors can increase glycine in CSF to potentiate NMDA receptor function.

Purine neurotransmitters ATP and adenosine

ATP and ADP act at P2X ionotropic and P2Y metabotropic receptors; adenosine modulates neuronal excitability and vascular tone.

Peptidergic neurotransmitters synthesis and action

Neuropeptides are synthesized as precursors in the soma, cleaved to active peptides, transported to terminals, released with classical transmitters, and act mainly at GPCRs to modulate signaling.

Endogenous opioids roles

Enkephalins and endorphins are peptide transmitters in pain pathways that bind opioid receptors to suppress nociceptive transmission.

Substance P function

Substance P is a neuropeptide released by primary pain afferents onto second-order anterolateral pathway neurons and contributes to pain signaling.

Nitric oxide neurotransmission

Nitric oxide is synthesized on demand by nitric oxide synthase, diffuses to nearby cells, modulates neurotransmission and vascular tone, and is not stored in vesicles.

Endocannabinoid signaling

Endocannabinoids such as anandamide and 2-AG are synthesized from membrane lipids in a Ca2+-dependent manner and act retrogradely on CB1/CB2 metabotropic receptors to modulate presynaptic release.

Reuptake transporters as drug targets

SERT, DAT, NET, and specific amino acid and choline transporters determine neurotransmitter clearance and are targeted by SSRIs, SNRIs, psychostimulants, and other drugs.

MAO inhibitors pharmacologic relevance

Inhibitors of monoamine oxidase increase monoamine levels and are used as antidepressants or to affect catecholamine metabolism.

COMT inhibitors clinical relevance

COMT inhibitors reduce peripheral breakdown of L-DOPA and are adjuncts in Parkinson disease therapy to increase central L-DOPA availability.

Synaptic vesicle cycle basics

Vesicles are loaded with transmitter, docked at active zones, undergo Ca2+-triggered fusion, and membrane components are retrieved by endocytosis for recycling.

Co-transmission concept

Neurons often release a classical small-molecule transmitter plus one or more neuropeptides that modulate the primary synaptic signal.

Second-messenger amplification in GPCR signaling

Metabotropic receptors activate G proteins to produce second messengers like cAMP or IP3 that amplify and prolong cellular responses beyond ion flux.

Somatodendritic vs terminal transmitter synthesis

Small-molecule transmitters are synthesized in terminals and packaged in small clear vesicles; neuropeptides are synthesized in soma and transported in large dense-core vesicles.

Long-term potentiation mechanism

Activity-dependent strengthening of synapses often requires NMDA receptor-mediated Ca2+ influx, activation of intracellular kinases, and increased AMPA receptor insertion.

Transporter blockade effects

Block of reuptake transporters increases synaptic transmitter concentration and prolongs receptor activation with therapeutic and adverse effects depending on the system.

Stroke excitotoxic cascade role of glutamate

Ischemia causes failure of ion gradients, excessive glutamate release, NMDA-mediated Ca2+ influx, and neuronal death; receptor antagonists can be neuroprotective in some contexts.

Drug modulation of cholinergic signaling

Acetylcholinesterase inhibitors increase ACh at synapses and are used in myasthenia gravis and to symptomaticly enhance cognition in Alzheimer disease.

GABAB receptor actions

GABAB receptors are metabotropic GPCRs that reduce neuronal excitability by activating K+ channels or inhibiting Ca2+ channels via G proteins.

Clinical relevance of serotonin receptors

Diverse 5-HT receptor subtypes mediate mood, gastrointestinal function, and vascular tone; many are drug targets for depression, migraine, and other disorders.

Dopamine receptor families and effects(D1-like receptors generally stimulate cAMP, D2-like receptors inhibit cAMP; these subtypes underlie different behavioral and motor effects.)