Intercellular Communication, Synapses

• Intercellular communication is a continuous process essential for maintaining a stable internal environment, known as homeostasis.
• This communication coordinates processes that enable organism growth, development, division, and organization of cells into tissues
• Cells send signals through substance secretion (exocytosis or gradient diffusion) and specific receptor reception (cellular surface or inside the cell).

Types of Intercellular Communication

• Gap junctions allow direct electrical activity propagation and chemical substance transport (up to MW 500) between adjacent cells.
• Autocrine communication cells release and bind to their own receptors, affecting cellular functions.
• Paracrine communication occurs when cells release chemical signals diffusing to neighboring cells through extracellular fluid (ECF).
• Endocrine communication involves cells releasing chemical signals into the blood.
• Synapse is a specialized intercellular junction

Intercellular Communication Specificity

• Gap junctions have direct information transport with a local character determined by anatomy.
• Autocrine communication involves diffusion through ECF, with a local character determined by receptors.
• Paracrine communication involves diffusion through ECF, also with a local character determined by receptors.
• Endocrine communication uses diffusion through ECF and has a general character as determined by receptors.
• Synaptic communication utilizes diffusion through ECF or direct means.

Synapse

• Synapses enable fast, well-targeted communication via action potentials (AP).
• Synapse is a connection between neurons and other cells
• Synapses feature postsynaptic membranes equipped with neurotransmitter receptors.
• Target tissue reactions are relatively fast and typically do not last long.

Synapse Classification

• Synapses are classified by signal transmission type (electrical or chemical).
• Synapses classified by contact elements (axo-dendritic, axo-axonic, or axo-somatic).
• Synapses are classified by the function they serve as (excitatory or inhibitory).

Charles Scott Sherrington

• Charles Scott Sherrington coined the term synapse in 1897.

Neuron Structure

• A Neuron's synapse includes structures like microtubules, neurofibrils, neurotransmitters, and receptors.

Specialized Synapses

• Found between sensory neurons and sensors.
• Present between motor neurons and muscles (motor end-plate).
• Synapses occur between neurons and secretory cells (endocrinology).

Synapse Structure

• Presynaptic neuron, synaptic cleft, and postsynaptic neuron comprise the specific structure of synapse

Electrical Synapse

• First described in the nervous system of lobsters.
• Enable electrical synchronization of many neurons in humans, especially in the hypothalamus and other brain regions.
• Electrical synapses have a reduced extracellular space of about 2 nm.
• Cytoplasms are continuous between cells.
• Information is carried by ions via gap junctions.
• Electrical synapses have minimum synaptic delay and bidirectional information flow.

Chemical Synapse

• A chemical synapse is the predominant type of synapse.
• Chemical synapses transmit impulses between pre- and postsynaptic neurons through neurotransmitter release (neuromediator).
• Neurotransmitter release from the presynaptic neuron is triggered by AP, followed by diffusion across the synaptic cleft, binding to receptors, and generation of postsynaptic AP.

Chemical Synapse Elements

• The presynaptic element (synaptic button) contains synaptic vesicles with neurotransmitters and mitochondria for neurotransmitter synthesis.
• The presynaptic membrane lacks myelin and has a non-excitable membrane.
• The synaptic cleft, filled with extracellular fluid (10-50 nm), separates the pre an post synapse.
• The postsynaptic element, located on a neuronal dendrite and or cell body.
• The postsynaptic membrane is the plasmalemma of the postsynaptic element.
• The subsynaptic membrane faces the presynaptic membrane and is non-excitable, containing receptors.

Chemical Synapse Transmission

• A unidirectional process from the presynaptic to the postsynaptic element through neurotransmitter release.
• Synaptic delay, about 0.5 ms.

Neurotransmitter Removal

• Occurs via enzymatic degradation (acetylcholine).

• Neurotransmitters are removed via reuptake back into the presynaptic element.

• Removed via diffusion into surrounding extracellular space and uptake into the postsynaptic element with subsequent degradation.

• Depolarization of the presynaptic membrane opens voltage-gated Ca2+ channels, increasing intracellular Ca2+ concentration.

• Synaptic vesicles fuse and release neurotransmitters into the synaptic cleft.

• Neurotransmitters diffuse across the synaptic cleft, generating an excitatory or inhibitory postsynaptic potential (EPSP or IPSP).

Neurotransmitter Release

• Neurotransmitter release from synaptic vesicles is due to the opening of voltage gated Ca2+ channels and subsequent exocytosis.
• Neurotransmitters bind to ligand-gated channels or receptors coupled to G proteins.
• Neurotransmitter removal occurs through diffusion or enzymatic degradation on the subsynaptic membrane

Postsynaptic Potential

• Neurotransmitter binding to receptors opens or closes relevant channels.
• Change membrane potential (postsynaptic membrane), potentially reaching threshold and initiating a new AP.
• Postsynaptic potentials are electrotonic, local, and graded responses.

EPSP

• Are depolarizations that increase permeability to Na+ and ↑ the probability of AP generation at the excitatory synapse

IPSP

• Are hyperpolarizations ↑ permeability to K+ and ↓ probability of AP generation at the inhibitory synapse

Regulation of Chemical Synapse Transmission

• Many EPSPs should be generated on the postsynaptic membrane for AP threshold to be reached
• A neuron in the CNS has thousands of afferent synaptic contacts, both inhibitory and excitatory.

Spatial Summation

• Several presynaptic neurons create synapses on a single postsynaptic neuron.
• Simultaneous neurotransmitter release from these neurons affects the postsynaptic neuron, potentially reaching the threshold for an AP.

Temporal Summation

• High-frequency APs on the presynaptic neuron lead to neurotransmitter accumulation in the synaptic cleft.
• Accumulation exceed degradation, neurotransmitter binds and reaches threshold EPSP → postsynaptic AP.

Neurotransmitters

• Neurotransmitters include catecholamines, acetylcholine, serotonin, y-aminobutyric acid, glutamic acid, and glycine.

General Requirements of Neurotransmitters

• Specific localization in neuronal synaptic vesicles.
• Specific biosynthesis (choline + AcCoA = Ach).
• Release by exocytosis.
• Binding to specific receptors (M or N receptors).
• Inactivation by synaptic enzymes (AChE).
• Simulation of the drug effect by its administration.

Criteria for Neurotransmitters

• Synthesis and storage in the presynaptic neuron (enzymes, substrates, transporters, synaptic vesicles).
• Presynaptic stimulation (usually electrical) releases the substance.
• Substance application under defined conditions evokes the same response as presynaptic stimulation.
• Agents blocking postsynaptic response to pre-synaptic stimulation also block the response from exogenous substance administration.
• Postsynaptic response to the substance should be short and well-defined.
• The substance tested as a neurotransmitter should share pharmacological characteristics with the endogenous neurotransmitter.

Types of Neurotransmitters

• Low Molecular-Weight Neurotransmitters and Neuromodulators: nitric oxide (NO), carbon monoxide (CO), acetylcholine (ACh), amino acids glutamic (Glu), aspartic (Asp), glycine (Gly), D-serine, AA derivatives serotonin, dopamine, adrenaline, noradrenaline, glutamate, γ-aminobutyric acid (GABA), and histidine.
• Purines: adenosine, AMP, ADP, ATP.
• Peptides: opioid peptides (endorphins, dynorphins, enkephalins), neurohypophyseal peptides (vasopressin, oxytocin), tachykinins substance P, neurokinin A, gastrins, cholecystokinins (CCKs), VIP, neuropeptide Y (NPY), bradykinin, angiotensin, CGRP.

Noradrenaline

• CNS: 18,000 neurons in the locus coeruleus regulate arousal, sleep-wake cycles, attention, memory, emotions, and stress.

• Present in PNS: postganglionic sympathetic fibers.

• Present in Adrenal medulla.

  Catecholamines

• Include dopamine, noradrenaline, and adrenaline.

Catecholamine Synthesis

• Tyrosine is converted to DOPA by tyrosine hydroxylase.
• DOPA is converted to dopamine by DOPA decarboxylase.
• Dopamine is converted to noradrenaline by dopamine-β-hydroxylase.

Adrenergic Receptors

• Alpha (α1 and α2) and beta (β1 and β2) which mediate the effects of catecholamines.

Acetylcholine

• CNS: Meynert nucleus (substantia innominata), reticular formation, and basal ganglia.
• PNS: preganglionic sympathetic fibers, preganglionic parasympathetic fibers, postganglionic parasympathetic fibers, some postganglionic sympathetic fibers (sweat glands), and somatic motor neurons.

Acetylcholine Degradation and Synthesis

• Acetyl-CoA + Choline is converts to Acetylcholine via choline acetyltransferase
• Acetylcholine broken down into Choline + Acetate via acetylcholinesterase

Cholinergic Receptors

• Nicotinic (N1 and N2) and muscarinic (M1,3,5 and M2,4) receptors mediate the effects of acetylcholine.

Dopamine

• Nuclei contain about 400,000 neurons in substantia nigra, tegmentum, and hypothalamus -project to hypothalamus, basal ganglia, prefrontal cortex, hippocampus.
• Important for motivation, reward, fear, prolactin secretion.
• Dopamine has its own receptors D1 – D5
• Progressive degeneration of dopaminergic neurons (subst. nigra) causes loss of dopaminergic innervation in the basal ganglia, leading to motor symptoms associated with Parkinson's disease-

Serotonin (5-HT)

• With only a few brainstem nuclei, raphe nuclei.
• Medulla nuclei project axons that modulate pathways of pain, activity of spinal cord interneurons, and motor neurons.
• Nuclei in the midbrain and pons innervate almost the entire brain.
• Combines with projections from the locus coeruleus to form part of the ascending reticular activating system (RAAS).

Gamma-Aminobutyric Acid (GABA)

• GABA is the predominant central nervous system inhibitory amino acid.
• 25-45% of all synapses in the vertebrate nervous system are GABAergic.
• GABA in the thalamocortical system mediates sleep spindle-related neuronal hyperpolarization.
• GABAergic neurons are in the brainstem and forebrain.
• In the reticular formation of the brain stem, they inhibit glutamatergic neurons of the ascending reticular activating formation.
• Synthesized from glutamate with the help of decarboxylating L-glutamic acid.

Glutamic Acid

• A principal excitatory neurotransmitter in the CNS.
• Glutamate receptors are widely distributed in the reticular formation of the brainstem; this seems to be the primary neurotransmitter of RAAS.
• Glutamatergic neurons form multiple synapses in the thalamus and cortex - release in the condition of alertness.

Glycine

• Glycine is an inhibitory neurotransmitter in the Spinal cord, the brainstem, and retina.
• Ionotropic receptors are coupled to Cl- channel (causes hyperpolarization of the membrane).
• Primarily in the gray matter of the spinal cord and it serves as the main neurotransmitter of inhibitory interneurons.
• Strychnine is an inhibitor of glycine receptor.
• Disinhibition of inhibitory interneurons causes a spreading of irritation and resulting convulsions.