The Nervous System: Neurons and Signal Transmission

Overview of the Nervous System

• Consists of 86 billion neurons and a quadrillion synaptic connections.
• Three main types of neurons: sensory, interneurons (in the brain), and motor neurons.

Neurons

• Composed of a cell body, nucleus, axons, dendrites, neurites, and a myelin sheath.
• Schwann cells with Ranvier nodes create the myelin sheath.
• Axons transmit information to dendrites.

Signal Transmission

• An electrochemical process, occurring partly via synapses using neurotransmitters.

Synaptic Function

• Neurotransmitters either excite or inhibit the next neuron.
• Inhibition balances brain activity and focuses information.
• Neurotransmitters are synthesized and stored in vesicles.
• When an action potential arrives, calcium channels open, allowing Ca2+ ions to enter.
• Vesicles merge with the presynaptic membrane, releasing neurotransmitters via exocytosis.
• Neurotransmitters bind to receptors on the postsynaptic membrane, opening or closing ion channels.
• This process leads to excitation or inhibition of the postsynaptic cell.
• Neurotransmitters are then removed from the synapse by glial cells or enzymatic degradation.

Neurotransmitters

• Released in the synapse and act on specific postsynaptic membrane receptors.
• They can also interact with presynaptic autoreceptors in some synapses.
• Many different kinds of neurotransmitters exist.

Types of Neurotransmitters

• Excitatory Amino Acids: Main excitatory neurotransmitters in the CNS, primarily glutamate, acting on various receptors.
• Inhibitory Amino Acids: Main inhibitory neurotransmitters like GABA, found throughout the CNS, and glycine, mainly in the spinal cord.
• Monoamines: Located in smaller neuron groups in the brainstem, projecting to the CNS and autonomic nervous system, binding to multiple receptors.
• Acetylcholine: Widely distributed across the nervous system, including neuromuscular junctions and the autonomic nervous system.
• Neuropeptides: Found throughout the nervous system and often released alongside other neurotransmitters, with over 50 identified.
• Individual ions (like zinc) and gaseous molecules (nitric oxide, carbon monoxide, hydrogen sulfide) can act as neurotransmitters.
• Glutamate is the most common excitatory neurotransmitter, while GABA is the most common inhibitory one restricting over 90% of synapses that don't use glutamate.

Receptors

• Typically specific to certain neurotransmitters.
• Directly linked to ion channels or membrane enzymes.
• Neurotransmitter binding either opens ion channels via intracellular enzyme cascades or modulates ion channel opening based on voltage changes (neuromodulation).
• Activated receptors return to a resting state after the neurotransmitter is removed.
• Some receptors undergo desensitization (reduced affinity) or sensitization (increased affinity).

Receptor Types

• Ionotropic: NMDA, AMPA, kainate
• Metabotropic: Coupled with G-proteins, triggering intracellular biochemical events that modulate synaptic transmission.

Types of Synaptic Transmission

• Axosecretory (axon to blood), axoaxonic (axon to axon), axodendritic (axon to dendrite), axoextracellular (axon to extracellular fluid), axosomatic (axon to soma), and axosynaptic (axon to another axon's terminal).

Neurodegeneration

• Fundamental aspects of neurodegenerative (ND) diseases: Neurons die or malfunction, progressive, related to aging, insidious onset, unclear etiology.
• Impact memory, thinking, orientation, calculation, learning, judgement, and movement.

Dementia in Europe

• Prevalence: ~9.3 million cases.
• Common causes: Alzheimer’s (50-70%) and vascular dementia (30%).
• Increases with age; affecting 32.4% of men and 48.8% of women by age 95.
• Public health priority is improved early diagnosis, treatment, and caregiver support.
• EU projects to enhance dementia understanding include EuroCoDe and the Joint Programme-Neurodegenerative Disease Research (JPND).
• National dementia strategies: France, Norway, UK, and Slovenia.

Diagnostic Methods for ND detection

• Protein aggregates accumulate in specific brain areas.
• Postmortem diagnostics are the most accurate.
• Biological markers are critical for early disease detection, identifying molecule cascade changes in disease progression.
• Amyloid plaques are extracellular proteins identified.
• Behavioral/neurological tests (PB, ALS & MS) and cognitive tests (AB) are important.
• PET scans visualize damage using labeled molecules targeting affected brain regions like L-DOPA for PB or β-amyloid targeting molecules for AB.
• By the time PET scans reveal damage, therapeutic interventions are often too late. MRI scans whole brains and can assess volume/activity changes in the brain.
• Diagnostic is often delayed despite marker advancements.

Biomarkers of ND detection

• Measured and evaluated as indicators of normal or pathological processes and pharmacological responses.
• Examples: Abeta fibrils and alpha-synuclein.
• RT-QuIC (real-time quaking-induced conversion) amplifies aggregates; uses a recombinant alphaSyn substrate + thioflavin T to detect aggregates via fluorescence.

Molecular ND Information

• Genetic information flows from DNA to RNA to proteins.
• Genes encode DNA info, which creates proteins.
• Transcript converts RNA to RNA
• mRNA codes for proteins.
• Issues which may occur: nucleocytoplasmic transport, RNA metabolism & RBP, proteostasis (aggregation), non-functioning oligodendrocyte, microglie, cytoskeletal/axonal transport, vesicle transport, excitotoxicity, mitochondrial damage, DNA repair, proteostasis, ROS.

Symptoms of Neurodegeneration

• Genomic instability, epigenetic changes & intercellular communication, decline in stem cells, cellular senescence, mitochondrial deterioration, altered nutrient sensing, lack of proteostasis & telomere erosion.

Standard Molecuar Last properties

• Aging, genetics, epigenetics & genomic disruption & transcription/ranslation
• Intercellular amyloid development, poor razgradnja proteins due to harmed proteasoma, reduced autophagy and razgradja proteins in lisosomih & mitochondrial disfunctioning
• Larger ROS release, perverted transport and ekscitotoxins

Genetics

• DNA sequencing has become faster and cheaper, but data processing bottlenecks remain.
• Example projects: 1000 Genomes, MINE (ALS DNA profiling). Technologies incl. Solexa.
• Nanopore sequentially pulls DNA through microscopic holes, identifies bases via ion flow disruptions using proteins & adapters.

PACBIO genetics

• A technique to get accurate circular readings on data

Compostion

mRNA-62% & lncRNA - 53% & miRNA -0.7%

Three Epigenetic Modifiers of Gene Expression

• DNA methylation, histone modification, RNA processes (silencing).
• DNA methylation and RNA processes change with aging, leading to DNA mutations and altered gene expression.
• Activation of retrotransposons, that can jump around the genome and alter it is also common with aging

Causes of GENE mutation-caused ND

• DNA damage accumulation, heterogenity loss due to poškodbe and epimutations /transcription interuption on poškodovanih & nevronsih funcik), senescence, or biasa normal operation.

Genetic DNA changes in proteins

• DNA quadrulepxes are energetically stable and can prevent or disrupt splicing via proteins bonding to them

Common transription protein changes

• Alternative coupling, posamezne genes can yield posamezne gene production by cut off extons, conserving introns or alternative extons. Some parts translated and there exists greater possibilities to translate the cut code.

SR protein changes

• Bind enhanced slicing spots and RRM and RS

MRNA Transport.

• It is transported due to dendrites which can locally create translations, also the MRNA becomes granule bound because MRNA bound proteins are capable of cohesion

Explore the nervous system's structure, including neurons, axons, and dendrites. Learn about signal transmission, the role of neurotransmitters and synaptic function. Understand the electrochemical process and how messages are transmitted between neurons.