Chemical Synapse and Neurotransmitter Classification

Chemical Synapse

• A chemical synapse is the junction between two neurons where neurotransmitters are released and received.
• The presynaptic neuron converts an electrical signal into a chemical signal, while the postsynaptic neuron converts the chemical signal back to an electrical signal.
• Neurotransmitters are chemical substances synthesized in a neuron and released during neuron excitation.
• Neurotransmitters are released from vesicles in the presynaptic terminal upon the arrival of an action potential.
• Calcium ions (Ca2+) play a crucial role in neurotransmitter release.
• The neurotransmitter binds to receptors on the postsynaptic membrane, triggering a change in the postsynaptic membrane potential.
• Neurotransmitter inactivation occurs through enzymatic catabolism or by reuptake into the presynaptic terminal or glial cells.

Neurotransmitter Classification

• Functional Classification:
  • Excitatory: Depolarize the postsynaptic membrane, increasing the likelihood of an action potential.
  • Inhibitory: Hyperpolarize the postsynaptic membrane, decreasing the likelihood of an action potential
  • Photoreceptors are an exception, where they are active during hyperpolarization.
• Location of Effects:
  • Direct (ionotropic): Bind to ion channels, directly affecting their opening or closing.
  • Indirect (metabotropic): Bind to receptors that activate secondary messenger systems, leading to indirect effects on ion channels.

Other Functions

• Neurotransmitters are deactivated in 3 ways:
  • Degradation by enzymes
  • Reuptake by glial cells or the presynaptic cell.
  • Diffusion away from the synapse.

Acetylcholine (ACh)

• ACh is synthesized from choline and acetyl coenzyme A (acetyl-CoA).
• Choline acetyltransferase (ChAT) is the rate-limiting enzyme in ACh synthesis.
• ACh is packaged into vesicles by a vesicular acetylcholine transporter (vAChT).
• ACh is broken down by the enzyme acetylcholinesterase.

ACh Function:

• Skeletal Muscle: Contraction
• Heart Muscle: Inhibition of contraction
• Other Functions: Cortical excitability, heart and skeletal muscle contraction, arousal and sleep, cognition and reward.

ACh Secretion:

• CNS: Cerebral cortex, hippocampus, brainstem.
• PNS: Neuromuscular junction of muscles, all preganglionic, parasympathetic, and postganglionic fibers of the autonomic nervous system (ANS).

Cholinergic Receptors:

• Nicotinic (N1/Nm): Found at the neuromuscular junction of skeletal muscles.
• Nicotinic (N2/Nn): Found in pre and postganglionic neurons of the parasympathetic NS, postganglionic neurons of the sympathetic NS.
• Muscarinic:: Found in various tissues, including the heart, smooth muscle, and glands.

Clinical Correlations:

• Alzheimer's Disease: Decreased ACh levels in the brain, particularly in the basal forebrain, affecting learning and memory.
• Myasthenia Gravis: Autoimmune disorder where nicotinic ACh receptors are destroyed, leading to muscle weakness and fatigue.
• Huntington's Disease/Huntington's Chorea: Caused by degeneration of ACh and GABA neurons, leading to involuntary movements and dementia.

Dopamine (DA)

• DA plays a role in movement, attention, learning, memory, arousal, sleep, behavior, cognition, and inhibition of prolactin production.
• DA is synthesized in the adrenal glands and the CNS (substantia nigra, VTA, hypothalamus, and some sympathetic ganglia)
• DA is inactivated by monoamine oxidase and catechol-o-methyltransferase.

Dopamine Receptors:

• D1: Working memory
• D3: Addiction behaviors
• D4: Wide functions in amygdala, hippocampus, pituitary gland, and retina.

Clinical Correlations:

• Parkinson’s Disease: Degeneration of dopaminergic neurons in the substantia nigra leading to tremors, rigidity, and akinesia.
• Schizophrenia: Increased activity at dopaminergic synapses related to the disease condition.
• Cocaine Drug Abuse: Cocaine inhibits the reuptake of DA and NE into nerve terminals, leading to an increase in their levels and a sense of euphoria.

Norepinephrine (NE)

• NE is an indirect-acting neurotransmitter (metabotropic) that plays a role in mood regulation, alertness, and vigilance.
• NE is synthesized in the locus coeruleus nuclei (in the brainstem), as well as in the limbic system and some areas of the cerebral cortex.
• NE is also secreted in the PNS, where it acts as the main neurotransmitter of postganglionic neurons in the sympathetic nervous system.

Clinical Correlations:

• Depression: Decreased NE activity is associated with depression.
• Mania: Increased NE activity is associated with mania.

Epinephrine (EPI)

• EPI can be synthesized in neurons of the adrenal medulla and transported back to neurons or used in tissues.
• The neurotransmitter released from the adrenal medulla.

Serotonin (5-HT)

• 5-HT is an indoleamine neurotransmitter synthesized from dietary tryptophan.
• 5-HT has both inhibitory and excitatory effects. It acts indirectly via second messengers and directly at 5-HT receptors.
• 5-HT is synthesized in the brainstem, particularly in the dorsal and medial raphe nuclei, and projects to various areas of the CNS like the hypothalamus, limbic system, cerebellum, pineal gland, and spinal cord.

Clinical Correlation:

• Depression and Insomnia: Low serotonin levels.
• Mania and OCD: High serotonin levels.
• Migraines: 5-HT agonists can prevent and abort migraines due to their vasoconstrictive and anti-inflammatory effects.

Glutamate

• Glutamate is the primary excitatory neurotransmitter in the CNS.
• Glutamate is derived from the Krebs cycle and is also taken up through glutamate reuptake.

Clinical Correlations:

• Alzheimer’s Disease: Overexcitation and glutamate-induced activation of NMDA receptors contribute to neuronal loss.
• Retina: Plays a role in light signal transduction, and is the primary neurotransmitter in the retina.

GABA

• GABA is an inhibitory neurotransmitter in the brain.
• GABA plays a role in anxiety, sleep, and motor control.

Clinical Correlations:

• Anxiety Disorders: Reduced GABA activity is associated with anxiety disorders.
• Sleep Disorders: GABA plays a role in regulating sleep-wake cycles.