disorders of neurotransmission

"Describe the role of sodium channels in action potentials."

"Sodium channels open in response to depolarization, allowing Na+ to enter the cell, which initiates the action potential."

"Explain how tetrodotoxin affects synaptic transmission."

"Tetrodotoxin blocks sodium channels, preventing action potentials and leading to paralysis."

"Describe the source of tetrodotoxin in certain fish."

"Tetrodotoxin is not synthesized by the fish itself, but by bacteria associated with the fish."

"Explain how tetrodotoxin affects sodium channels."

"Tetrodotoxin inhibits sodium channels by binding to them and blocking the pore, preventing sodium ions from entering the nerve cell, which inhibits action potentials."

"Define the role of sodium channel alpha subunits in mammals."

"Sodium channel alpha subunits are encoded by 9 genes in mammals and are essential for the expression of functional sodium channels in excitable tissues."

"How are sodium channel alpha subunits structured?"

"Sodium channel alpha subunits are organized into four homologous domains, each containing six transmembrane segments, with segments 1-4 forming the voltage sensor and segments 5-6 forming the pore region."

"Explain the function of sodium channel beta subunits."

"Sodium channel beta subunits modulate the kinetics and voltage dependence of sodium channel activation and inactivation, and they form complexes with alpha subunits in excitable cell membranes."

"Describe the structural characteristics of sodium channel beta subunits."

"Sodium channel beta subunits have an N-terminal extracellular immunoglobulin-like fold, a single transmembrane segment, and a short intracellular segment."

"Discuss the diversity of sodium channel subunits."

"Sodium channel subunits exhibit diversity in their structure and function, with alpha subunits being encoded by various genes and beta subunits resembling cell adhesion molecules."

"Explain the significance of sodium channel mutations in human health."

"More than 1,000 mutations in human sodium channels have been identified, leading to genetic diseases such as periodic paralysis, cardiac arrhythmia, epilepsy, and chronic pain."

"Describe the impact of NaV1.1 mutations in Dravet syndrome."

"In Dravet syndrome, loss-of-function mutations in NaV1.1 channels impair the excitability of GABAergic inhibitory neurons, leading to hyperexcitability in neural circuits and causing epilepsy."

"How do sodium channel mutations contribute to increased cellular excitability?"

"Sodium channel mutations can cause a gain-of-function effect, leading to unexpected mechanisms of increased cellular excitability at both molecular and cellular levels."

"Define the role of NaV1.1 in the central nervous system."

"NaV1.1 is broadly expressed in the central nervous system and may be preferentially expressed in inhibitory GABAergic neurons."

"Explain the relationship between sodium channel beta subunits and alpha subunits."

"Sodium channel beta subunits are promiscuous in their associations with alpha subunits, lacking strict specificity for functional associations in different tissues or cell types."

"Describe the primary structure of sodium channel alpha subunits."

"Sodium channel alpha subunits are composed of approximately 2000 amino acid residues and share more than 50% amino acid sequence homology among NaV1.1 to NaV1.9."

"Discuss the role of the voltage sensor in sodium channels."

"The voltage sensor in sodium channels is formed by segments 1 through 4 of each domain, with segment 4 (S4) containing a high concentration of positive charges."

"Explain how tetrodotoxin differs from other sodium channel toxins."

"Unlike some toxins that activate sodium channels, tetrodotoxin specifically blocks sodium channels, preventing sodium ion entry and action potential generation."

"Describe the primary cause of Dravet's syndrome."

"Dravet's syndrome is primarily caused by nonsense mutations in the SCN1A gene, leading to severe impairments in sodium channel function."

"Explain the relationship between SCN1A mutations and generalized epilepsy with febrile seizures plus."

"Approximately two dozen SCN1A mutations are associated with generalized epilepsy with febrile seizures plus, which is characterized by short-lasting tonic-clonic seizures triggered by fever."

"Define the clinical phenotypes associated with NaV1.1 mutations."

"NaV1.1 mutations are linked to various clinical phenotypes, including severe myoclonic epilepsy of infancy (Dravet's syndrome) and generalized epilepsy with febrile seizures plus."

"How do NaV1.1 mutations affect channel function in epilepsy patients?"

"NaV1.1 mutations can either prevent channel expression or severely impair channel function, leading to more detrimental forms of epilepsy."

"Describe the characteristics of benign familial neonatal-infantile seizures."

"Benign familial neonatal-infantile seizures is an autosomal dominant disorder characterized by febrile seizures that begin within 4 months after birth and typically remit within the first year without neurological deficits."

"Explain the significance of NaV1.2 mutations in epilepsy research."

"NaV1.2 mutations are associated with inherited epilepsy and are important for understanding the mechanisms of epilepsy, which may aid in the development of new antiepileptic drugs."

"What challenges do researchers face in developing new antiepileptic drugs?"

"One major challenge is that 20-30% of epilepsy patients are pharmaco-resistant, meaning they do not respond to at least two different antiepileptic drugs."

"Describe the impact of the C121W mutation in the SCN1B gene."

"The C121W mutation in the SCN1B gene disrupts a disulfide bond necessary for proper protein folding, leading to altered sodium channel function and potential hyperexcitability."

"How do mutations in sodium channel beta subunits affect epilepsy?"

"Mutations in sodium channel beta subunits, such as SCN1B, can lead to altered inactivation properties of sodium channels, which may contribute to increased neuronal excitability and seizures."

"Explain the complexity of the relationship between genetic mutations and epilepsy phenotypes."

"The relationship between genetic mutations and epilepsy phenotypes is complex, as a single mutation can result in a wide range of clinical manifestations influenced by the individual's unique genomic background."

"Describe the role of myelin in the nervous system."

"Myelin is an insulating lipid-rich structure that forms multiple membrane layers around axons, providing electrical insulation necessary for accelerated and efficient transmission of electrical signals along both central and peripheral nervous system axons."

"Explain the process of saltatory conduction."

"Saltatory conduction allows nerve impulses to travel rapidly by enabling action potentials to 'jump' from node to node along myelinated axons, significantly increasing the speed of transmission compared to continuous propagation."

"Define multiple sclerosis (MS)."

"Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by the immune system attacking myelin-producing cells, leading to demyelination, neuronal damage, and a variety of neurological symptoms."

"How does demyelination affect neurological function in multiple sclerosis?"

"Demyelination in multiple sclerosis leads to dysfunctions that result in sensory, motor, and cognitive impairments, causing a wide range of neurological symptoms and disabilities."

"What are some common symptoms experienced by multiple sclerosis patients?"

"Common symptoms of multiple sclerosis include visual problems, changes in sensation, weakness, spasticity, pain, fatigue, depression, and paralysis."

"Discuss the epidemiology of multiple sclerosis."

"The prevalence of multiple sclerosis varies by race and geographical location, with higher rates observed in the Caucasian population of northern Europe compared to southern Europe, and approximately 2.5 million patients worldwide."

"Explain the potential environmental factors contributing to the development of multiple sclerosis."

"Environmental factors such as low vitamin D levels, smoking, childhood obesity, and Epstein-Barr virus infection are believed to play a role in the development of multiple sclerosis."

"Describe the immune response involved in multiple sclerosis."

"In multiple sclerosis, the immune system reacts against myelin, leading to inflammatory lesions in the CNS, loss of oligodendrocytes, and axonal degeneration, primarily driven by T-lymphocytes."

"How does the gender ratio of multiple sclerosis patients compare?"

"Multiple sclerosis affects females approximately three times more than males, indicating a significant gender disparity in the disease's prevalence."

"What is the significance of oligodendrocytes in the context of multiple sclerosis?"

"Oligodendrocytes are crucial for myelin production in the CNS, and their loss due to autoimmune attacks in multiple sclerosis leads to demyelination and subsequent neurological dysfunction."

"Explain the role of T-cells and B-cells in the inflammatory process of multiple sclerosis."

"The inflammatory process in multiple sclerosis is primarily mediated by T-cells, which infiltrate the CNS, but recent therapies targeting B-cells suggest that they also play a role in the disease."

"How does aging influence the progression of multiple sclerosis?"

"Aging is considered a risk factor for the progression of multiple sclerosis, as the disease typically starts in young people but can worsen as they age, despite having a life expectancy close to average."

"Describe the characteristic pathological change observed in the brains of patients with multiple sclerosis (MS)."

"The most characteristic pathological change in MS brains is the formation of large confluent demyelinated plaques in the white and grey matter."

"Explain the process of demyelination in MS lesions."

"Demyelination in MS lesions is a selective process that affects myelin sheaths and oligodendrocytes, while axons and neurons are partially preserved, especially in the early stages of lesion formation."

"How does the maturation of MS lesions affect axonal integrity?"

"With the maturation of MS lesions and the chronicity of the disease, substantial axonal loss occurs, which contributes to irreversible neurological deficits."

"What role do astrocytes play in established white matter lesions in MS?"

"In established white matter lesions, astrocytes form glial scars, which are a defining feature of the disease process in multiple sclerosis."

"Identify areas in the brain where extensive demyelination occurs in MS."

"Extensive demyelination in MS is seen in grey matter areas such as the cerebral and cerebellar cortex, deep grey matter nuclei, and the grey matter of the spinal cord."

"Discuss the potential for remyelination in MS lesions."

"Studies have shown evidence for remyelination in up to 70% of MS lesions, indicating that myelin sheaths can be re-established along demyelinated axons, restoring structure and function."

"Define the typical progression of multiple sclerosis in patients."

"The majority of patients with multiple sclerosis start with a relapsing remitting phase (RRMS), which later converts into a secondary progressive phase (SPMS). In primary progressive MS, the relapsing stage is absent, and the disease progresses uninterrupted from onset."

"How does inflammation change throughout the stages of MS?"

"Inflammation is present at all stages of MS, but it is more pronounced in acute or relapsing MS compared to the progressive stage, where new lesions become rare."

"What is the relationship between active demyelination and microglia in MS?"

"Active demyelination in MS is associated with a rim of activated microglia at the border between cortical plaques and normal appearing grey matter, suggesting that cortical demyelination in the progressive stage may be induced by soluble factors through microglia activation."

"Explain the significance of blood-brain barrier leakage in early stages of MS."

"In early stages of MS, inflammation is associated with profound blood-brain barrier leakage, indicating the infiltration of new waves of inflammatory cells into the central nervous system from the circulation."

"Describe the types of white matter lesions observed in MS brains."

"Different types of white matter lesions in MS include classical active lesions, slowly expanding lesions, and inactive lesions, with classical active lesions characterized by profound lymphocytic inflammation and macrophage infiltration."

"What distinguishes classical active lesions from those in the progressive stage of MS?"

"Classical active lesions are most frequent in acute or relapsing MS and are characterized by significant inflammation, while the majority of active lesions in the progressive stage differ from these classical lesions."

"Discuss the factors influencing multiple sclerosis."

"Multiple sclerosis is influenced by both genetic and environmental factors, and the absence of specific etiological targets for prevention and therapy has led to treatments that slow disease progression but do not cure it."

"Describe the role of GWA studies in understanding multiple sclerosis (MS)."

"GWA studies have identified more than 150 single nucleotide polymorphisms associated with MS susceptibility, linking specific gene polymorphisms to the disease."

"Explain the significance of the odds ratio in the context of genetic risk factors for MS."

"The odds ratio for most identified gene polymorphisms related to MS is small, around 1.1–1.2, indicating that each polymorphism contributes only a very small increase in risk."

"Define the types of therapies used in the treatment of multiple sclerosis."

"Treatment of MS includes disease-modifying therapies that are MS-specific and symptomatic therapies that address neurological dysfunction symptoms."

"How have disease-modifying therapies for MS evolved over time?"

"As the number and efficacy of disease-modifying therapies have increased, there is growing interest in early treatment to prevent long-term disability."

"Describe the mechanism of immune reconstitution therapies for MS."

"Immune reconstitution therapies, such as alemtuzumab and cladribine, deplete components of the immune system to allow for renewal, aiming for enduring immunological effects."

"Explain the purpose of symptomatic therapies in MS treatment."

"Symptomatic therapies are used to alleviate symptoms of MS, such as bladder dysfunction and neuropathic pain, and are not specific to MS."

"What are some specific symptomatic therapies licensed for MS?"

"Licensed symptomatic therapies for MS include sativex for spasticity and fampridine for walking difficulties."

"How does the prevalence of sleep difficulties relate to MS?"

"The prevalence of sleep difficulties increases with MS disease duration, and poor sleep is associated with higher rates of anxiety, depression, and fatigue."

"Describe the process of calcium entry into presynaptic cells during depolarization."

"Depolarization of the terminal membrane causes calcium channels to open, allowing Ca2+ to enter the presynaptic cell."

"What are omega-conotoxins and their role as calcium channel toxins?"

"Omega-conotoxins are peptides that block calcium channels, affecting neuromuscular junctions and preventing action potentials without interfering with cellular functions."

"Explain how venomous cone snails use omega-conotoxins to capture prey."

"Venomous cone snails use a harpoon-like tooth to inject omega-conotoxins into fish, immobilizing them for easier capture and digestion."

"Define the structure of omega-conotoxins."

"Omega-conotoxins are peptides consisting of 24-30 amino acids with three disulfide bonds."

"Describe the effects of omega-conotoxins on skeletal muscle."

"Omega-conotoxins GVIA, GVIB, and GVIC block the neuromuscular junction of skeletal muscle by inhibiting calcium channels."

"Describe the specificity of omega conotoxins in mammalian systems."

"Omega GVIA and omega MVIIA are remarkably specific for voltage-gated calcium channels that contain the alpha 1B subunits."

"Explain the role of omega conotoxins in synaptic transmission."

"Omega conotoxins are widely used tools for blocking synaptic transmission and studying synapses due to their specificity for calcium channels present at presynaptic termini."

"Define Lambert Eaton myasthenic syndrome (LEMS)."

"LEMS is an autoimmune neuromuscular junction channelopathy caused by antibodies against voltage-gated calcium channels (VGCCs), leading to symptoms like muscle fatigue and weakness."

"How does LEMS differ from Myasthenia gravis in terms of electrophysiological abnormalities?"

"LEMS exhibits distinctive electrophysiological abnormalities in repetitive nerve stimulation that differ from those seen in Myasthenia gravis."

"What is the prevalence of LEMS compared to Myasthenia gravis?"

"LEMS has a world-wide prevalence of 2–4 per million, which is approximately 46 times less than that of Myasthenia gravis."

"Describe the typical age of onset for LEMS."

"The median age of onset for LEMS is around 50–60 years, but it can also affect children."

"Explain the gender predominance observed in LEMS cases."

"A female predominance is found in individuals diagnosed under 45 years, while a male predominance is observed in those diagnosed after 60 years."

"What are the main symptoms of LEMS?"

"The main symptoms of LEMS include proximal muscle weakness, autonomic features, and areflexia."

"How does the symptom progression in CA-LEMS compare to NT-LEMS?"

"The disease progression is much more malignant in CA-LEMS than in NT-LEMS, with CA-LEMS typically implicating legs and arms at onset."

"What autonomic dysfunction symptoms are common in LEMS patients?"

"Common autonomic dysfunction symptoms in LEMS patients include dry mouth, constipation, erectile dysfunction, loss of sweating, orthostatic hypotension, and pupillary abnormalities."

"Identify the most common malignant carcinoma associated with CA-LEMS."

"The most common malignant carcinoma associated with CA-LEMS is small cell lung carcinoma (SCLC), which is related to smoking."

"What types of tumors are associated with LEMS?"

"Other tumors associated with LEMS include non-small cell lung carcinomas, prostate carcinoma, and thymoma."

"How have pathogenic autoantibodies improved the diagnosis of LEMS?"

"The discovery of pathogenic autoantibodies against VGCC has facilitated the diagnosis of LEMS and enhanced understanding of its pathophysiological mechanisms."

"What type of VGCCs do most antibodies in LEMS patients target?"

"Most antibodies in LEMS patients are directed against P/Q-type VGCCs, which cause the majority of clinical symptoms."

"What is the detection rate of antibodies against P/Q-type VGCCs in LEMS patients?"

"Antibodies against P/Q-type VGCCs are traditionally detected in 85–90% of patients with LEMS, and up to 100% in LEMS patients with SCLC."

"Describe the role of antibodies in Lambert Eaton Myasthenic Syndrome (LEMS)."

"Antibodies against various types of voltage-gated calcium channels (VGCCs), including N-type and L-type, are found in a significant percentage of LEMS patients, often alongside P/Q-type VGCC antibodies. These antibodies target VGCCs on motor nerve terminals, contributing to the symptoms of LEMS."

"Explain the treatment approach for patients diagnosed with LEMS."

"Treatment for LEMS typically involves two components: addressing any known tumors and providing symptomatic management. Surgical removal of tumors can alleviate symptoms, likely by reducing VGCC antibodies and the autoimmune response."

"How does 3,4-diaminopyridine (3,4-DAP) function as a treatment for LEMS?"

"3,4-DAP blocks certain voltage-gated potassium channels, prolonging nerve terminal depolarization and increasing acetylcholine (ACh) release from nerve terminals, compensating for reduced release due to less active VGCCs."

"Define botulism and its causes."

"Botulism is a rare but serious paralytic illness caused by botulinum neurotoxin produced by the bacterium Clostridium botulinum. It can occur through foodborne ingestion, infant consumption of spores, or wound infections."

"Explain the symptoms associated with botulism."

"Symptoms of botulism include flaccid paralysis starting in the head, neck, and upper extremities, with potential ophthalmological dysfunction. Severe cases may lead to paralysis of the diaphragm and intercostal muscles, resulting in respiratory collapse."

"Describe the structure of botulinum neurotoxin A (BoNT A)."

"BoNT A is a large protein molecule of approximately 150 kDa, consisting of a heavy chain and a light chain, with components for protease activity, membrane translocation, and neuro-acceptor binding."

"What is the tri-phasic mode of intoxication by botulinum neurotoxin (BoNT)?"

"The tri-phasic mode of intoxication by BoNT involves the proteolysis of one of three proteins in the SNARE complex, which is essential for neurotransmitter release."

"How do botulinum neurotoxins affect the SNARE complex?"

"Botulinum neurotoxins proteolyze proteins within the SNARE complex, which includes synaptobrevin, syntaxin, and SNAP-25, disrupting the process of neuroexocytosis."

"What is the significance of calcium influx in the synaptic vesicle cycle?"

"Calcium influx is critical for the fusion of synaptic vesicles with the presynaptic membrane and is also important for the mobilization of vesicles in preparation for fusion."

"Discuss the importance of screening for tumors in LEMS patients."

"All LEMS patients are screened for the presence of tumors because most have concomitant cancers, and identifying these tumors is crucial for effective treatment."

"Describe the process that occurs when an excitatory neurotransmitter binds to its receptor in a postsynaptic cell."

"Upon binding, the receptor opens, allowing Na+ to enter the postsynaptic cell, leading to depolarization and the firing of an action potential."

"Explain the role of curare as a muscle relaxant."

"Curare is a non-depolarizing muscle relaxant that blocks nicotinic receptors on the postsynaptic membrane of the neuromuscular junction, preventing muscle contraction."

"Define a-bungarotoxin and its effects on the neuromuscular junction."

"A-bungarotoxin is a polypeptide toxin that irreversibly blocks the neuromuscular junction by binding to the alpha subunits of the nicotinic acetylcholine receptors, acting as a powerful antagonist of acetylcholine."

"How does myasthenia gravis affect neuromuscular transmission?"

"Myasthenia gravis is an autoimmune disease characterized by antibodies against AChRs, MuSK, or LRP4, leading to impaired neuromuscular transmission and fluctuating muscle weakness."

"Explain the significance of the clustering of AChRs at the neuromuscular junction."

"Clustering of AChRs at the NMJ is essential for effective neuromuscular transmission and is mediated by the agrin-LRP4-MuSK signaling pathway."

"Describe the safety margin of neuromuscular transmission."

"The safety margin is defined as the ability of neuromuscular transmission to remain effective under various physiological conditions, ensured by a surplus of both ACh and AChRs."

"What is the typical structure of nicotinic acetylcholine receptors in the central nervous system?"

"In the CNS, the typical structure of nicotinic acetylcholine receptors consists of a pentameric protein usually made up of 2 types of alpha subunits and 3 types of beta subunits."

"How does neural agrin contribute to the function of AChRs at the NMJ?"

"Neural agrin activates MuSK through binding with LRP4, which is essential for the clustering and maintenance of AChRs at the neuromuscular junction."

"Identify the main toxin in tubocurare and its historical use."

"The main toxin in tubocurare is D-tubocurarine, which was introduced into anaesthesiology in the early 1940s as a muscle relaxant for surgery."

"Describe the distribution of nAChRs in the postsynaptic membrane at the NMJ."

"nAChRs are spatially restricted to the area surrounding the openings of post-junction folds and partially down the sides of the infolded membrane, but are excluded from the trough of post-junctional folds."