MCB 165

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  1. Chlorpromazine
    • 1st antipsychotic drug
    • D2R antagonist
    • produces sedation, indifference to aversive stimuli; calms down Schizophernia, mania, and psychosis behaviors
  2. Neurological Disorders
    • Physical disorder in the N.S.
    • Physical basis that can be observed in the brain having surgical/ treatment 
    • degeneration and atrophy is visible
  3. Psychiatric (Mental) Disorders
    • Abnormalities of thoughts, feeling, and behaviors 
    • use DSM-V to classify and diagnose disorders 
    • are subjective w/ no obvious physical changes
    • classification based on ppl record or observation
  4. Basic research
    Understanding the fundamental basis of something
  5. Clinicial Research
    Patient-orientated, direct interaction w/ human subjects
  6. Translational Research
    Applies findings from basic science to clinical setting
  7. Heritability
    How much of the disease can be attributed to a genetic factor
  8. brain disorder can occur based on:
    • Heritability (genetic factors)
    • environmental factors (immune challenge or toxin affecting dev of brain )
    • Stochasticity in dev. Process (random things happening during dev that impact risk)
    • somatic mutation (DNA alterations after fertilization)
    • epigentic modification (gene expression changes)
  9. Mendelian Heritability
    • Single gene inheritance
    • autosomal dominant or autosomal recessive
  10. Non-Mendelian Heritability
    Multiple genes inheritance
  11. Most psychiatric disorders are caused by
    Multiple genetic factors that each alone increases susceptibility
  12. GWAS is used to
    Identify candidate suspectibilty genes for psychiatric disorders by comparing SNPs that show most association with disorder in affect vs unaffected population
  13. What are the 3 types of validities for a disease model
    • Construct validity 
    • Face validity 
    • predictive validity
  14. Construct validity
    Disease relevance of the methods by which a model is constructed
  15. Face Validity
    The model recapitulates important anatomical, biochemical, neuropathological or behavioral features of the human disease
  16. Predictive validity
    The model responds to treatment in a way that predicts the effects of those treatments in humans
  17. Cell culture (in vitro)
    Immortalized cell lines, from embryonic mice
  18. Animal models (in vivo)
    • Use living organisms 
    • advantage: study manipulations in an intact n.s. Using behavior 
    • disadvantage: unclear how translatable finding are from animals to humans
  19. Stem Cell
    • Advantage: able to preserve patient specific genetic info
    • disadvantge: not as well controlled as inbred animal models; can only study molecular and cellular level processes
  20. Traditional KO
    Disrupt an endogenous gene; cause loss of fxn mut.
  21. Transgenic mice
    • Express an exogenous gene
    • 1. GFP: label cells and visiualzation 
    • 2. Cre recombinase: express specific cell types to manipulate
  22. Conditional KO
    • Disrupt an endogenous gene in specific cell types 
    • Cre/ lox P system
  23. Human pluripotent stem cells
    • Fibroblast cells -> in vitro programming -> iPSCs -> differentiation with tx factors -> neurons 
    • used as a in vitro disease model or cell source for transplantation therapy
  24. Genome editing, Cas9
    Recognizes and cleaves invasive DNA as part of the adaptive bacterial immune response
  25. Serotonergic projections from
    Raphe nucleus
  26. DAergic projections from
    SNc (motor control) & VTA (reward/addiction)
  27. Neuropharmacology
    The study of drugs specifically employed to affect the nervous system
  28. Affinity
    • The concentration of a drug required to bind a given target 
    • Ki or IC50
    • lower values = tighter binding, higher affinity
  29. Efficacy
    • The ability of a drug to produce a biological response upon binding to a target
    • measured with dose-response curve 
    • want low [ ]
    • can measure between efficacy and toxicity
  30. Potency
    Combine affinity and efficacy
  31. Specificity
    How selective the drug is for a particular target
  32. dirty drugs
    • Bind to multiple targets 
    • can cause unwanted SE but also can be beneficial (more affective for treating psychosis with less SE since disorders can target many receptors and transporters)
  33. Drug action
    Molecular changes produced by a drug when it binds its target
  34. agonist
    Activates receptor
  35. partial agonist
    Binds and activates a receptor but only has partial efficacy
  36. antagonist
    Prevent/ blocks the action of an agonist
  37. inverse agonist
    Binds to the same site of the agonist but has an opposite effect
  38. Pharmacodynamics
    What the drug does to the body, including intended and unintended effects
  39. Pharmacokinetic
    • What the body does with the drug 
    • absorption, distribution, metabolism, excretion
  40. tolerance
    Diminish response to a drug
  41. Sensitization
    Enhanced drug effect
  42. blood brain barrier
    Prevents blood from getting into the brain, but can be problematic to get drug to brain
  43. drug development
    • 1. Select molecular target 
    • 2. Use biochemical or cell-based assay to identify a drug candidate 
    • 3. Use animal model to optimize PK
    • 4. Test in human clinical trials
  44. Neurotransmitter
    • Each NT has specific machinery for its synthesis, vesicle packaging, and reuptake/ degeratation
    • many drugs modulate NT levels or receptors
  45. NT Receptors
    • Iontropic 
    • metabotrophic
  46. ionotrophic receptor
    Direct ligand-gated ion channels
  47. metabotrophic receptor
    7 transmembrane spanning domains; signal via 2nd messenger, slow synaptic transmission
  48. GABAaR
    Pentamer consisting of 2α, 2β, and 1γ subunits
  49. Drugs targeting GABAaR
    • Subunits are selectively expressed in diff brain regions 
    • and in diff inhibitiory synapses (dendritic, perisomatic, axonal)
    • GABA systme is targeted by a # of different drugs for several diff disorders
  50. ASD classified by DSM-V
    • Persistent dificits in social communication and social interactions
    • restricted, repetitive patterns of behavior, interest, or activities (speech, mnct, hyper/ hypo- reactivity to sensory input)
    • symptoms present in early childhood
  51. ASD symptoms
    • Restricted interest 
    • altered social communication
    • altered react it to sensory stimuli
    • resistance to change
  52. What can be used as a quantitiative biomarkers before formal diagnoses of ASD at 6mo of age ?
    • Eye tracking
    • normal: babies focus on face and eyes
    • ASD: look at mouth and hands
  53. The Austism Spectrum is highly heterogeneous
    • From severe (non-verbal, motor stereotypes, self-injurious, ID) to hi-fxnl (savant, above ave intelligence, restricted/ obscure interest)
    • w/in spectrum have varying degrees of severities of each component
    • other psychiatric, behavioral, and physical symptoms associated with ASD
  54. Genetics of ASD
    • monogenetic Syndromic disorder (FXS)
    • De novo mut (not inherited)
    • common variants of small effects combined will enhance or converge ASD
  55. What are the synaptic fxns focused in ASD risk genes?
    • Cell adhesion molecules 
    • scaffolding proteins 
    • signaling transduction proteins
    • translational machinery
  56. How is protein translation common in pathophysiological in ASD?
    • Translational machinery important for regulating synaptic strength and plasticity 
    • too much or too little can be detrimental to synapse
  57. What are the environmental risk associated with ASD?
    • Immune dysregulation -> can impact synaptic fxn
    • maternal immune inactivation
  58. See deficits in synaptic pruning in ASD
    EXPLAIN EXPERIMENT
    • During development, have sig overgrowth of of synaptic connections and then get pruned during plasticity to refine synaptic connections 
    • ASD failed to prune
  59. What are the ways to model ASD in mice?
    • Mutation in single gene
    • mutation in chromosome region 
    • maternal immune challange
  60. What are the mouse behaviors observed that have face validity to ASD?
    • Ultraconic vocalization 
    • Reciprocal social interactions
    • social approach 
    • repetitive behaviors
  61. What are the brain regions associated with ASD?
    • Cerebellum: motor learning, social behavior 
    • Basal Ganglia: repetitive behaviors 
    • Cerebral cortex: social cognition, lang atten, sensory processing
  62. Syndromic disorder
    Affects both the brain and body, complex neurological and psychiatric problems
  63. Pathophysiology of Syndromic disorders
    • Neurodevelopmental disorders associates with known genetic causes (mut in single gene/ gain/loss of fxn in known chromosomal region)
    • onset in infancy and early childhood
    • Cause a "syndrome" of neurological, psychiatrically medical problems
    • reletively rare, but can be debilitating 
    • no cures and very few approved, eventhough have "rescue mice models"
  64. examples of Syndromic disorders
    • FXS (fmr1)
    • Tuberous Sclerosis Complex (TSC 1/2)
    • Down Syndrome (trisomy of chromosome 21)
    • Rett Syndrome (MECP2)
    • Angelman Syndome (UBE3A)
  65. gain or loss of fxn in Syndromic disorders
    • Can be both detrimental and result in overlapping phenotypes 
    • may lead to homeostatic responses that decrease the flexibility of the network, unable to restore level of balance and range outside optimal window
  66. What are the large scale changes in gene and protein expression in Syndromic disorders
    • Protein production (Tsc 1/2, PTEN, FMRP)
    • protein degration (Ube3a- ubiquitin ligase)
    • gene expression (MeCP2 epigenetic regulator)

    affect brain and body due to mutations/changes that globally regulate levels of protein/ gene regulations
  67. What are the genetic components of TSC?
    • Tsc1 and Tsc2; two diff genes on separate chromosomes (loss of fxn)
    • autosomal dominant, 100% penetrance
  68. What are the clinical manifestion of TSC?
    • Brain: cortical tubers, giant cell astrocytomas
    • body: affecting eyes, heart, kidney, lungs, skin, behavior 

    mutation in gene have both structural and behaviral and psychiatric problems
  69. Cortical tuber in TSC
    • Structural abnormablities that reflects early deve processes gone wrong in brain
    • made of a mixture of cell bodies and glia -> suggest there was a problem in differentiation
    • becomes a site of epiletogensis
  70. What are the clinical manifestion in neurological/ behavioral from TSC?
    • Seizures
    • mental retardation and learning difficulties
    • sleep disorder
    • austism and behavioral difficulties 
    • giant cell astrocytoma
  71. How does TSC1/2 affect mTOR signaling?
    • Negatively regulates mTOR signaling 
    • loss of fxn in one of these genes destabilize the other which causes over a ctivatean of mTOR -> too much protein syn and translation
  72. What does TSC2 +/- (heterozygous mut) show?
    It shows deficits in learning and memory, measured behavior in Morris water maze
  73. TSC models affected in synaptic plasticity
    • Learning deficits suggest to look at synaptic site of hippocampus
    • Synaptic plasticity is altered
  74. What are the synaptic changes in TSC when testing LTP?
    • Enhanced response to eLTP stimulus
    • suggest learning association that aren't meaningful (bc synapses are very easily potentiated)
  75. What are the synaptic changes in TSC when testing LTD?
    Loss of mGluR-LTD
  76. What happens when deleting TSC1 from forebrain excitatory neurons?
    • Mice has seizures
    • suggests that there are changes in these excitatory neurons that is causing severe 
    • used conditional KO Tsc1XCamkIIa-Cre mice from forebrain neurons and then given kinase acid to induce seizure 

    • control: recovered form seizure in hrs
    • CKO: continued to have seizures, died
  77. What happens to Tsc1 KO (mutation in Tsc1) hippocampal cultures?
    • Neurons are hyperactive: with high patterns correlated to epileptic activity, recapitulating phenotype of disease in dish
    • Neurons have reduced inhibitory synaptic fxn: increase E/I synaptic ratio in KO inbalance
  78. What are the behavioral phenotypes in Tsc 1 +/- and Tsc2 +/-?
    • Show reduced social interactions 
    • autistic phenotype 
    • model: social deficit monitored interaction of mice
  79. What does cerebellum-specific KO of Tsc1 cause?
    • Cause social abnormalities; recapitulate autistic behaviors 
    • social interaction ↓
    • Reverse learning ↓
    • grooming ↑
    • stereotypies (communication) ↑
  80. Treatment for TSC
    • Rapamycin: a strong potent inhibitor of mTOR signaling
    • improves outcomes in cerebeller-specific KO TSC1 mice 
    • restores synaptic balance and E/I ratio
    • reduces size of tuber and restore normal processes that can restor structural phenotypes
  81. What are the known causes for epilepsy?
    genetic disorder, infectious disease, traumatic brain injury, brain tumors, led poisoning
  82. What are the risk associated with children with epilepsy ?
    Learning disabilities, developmental day, and intellectual disability
  83. Seizure
    • An acute abnormal, highly synchronous period of electrical activity in a restricted brain region 
    • last sec -> mins
    • can happen once and never again
  84. Epilepsy
    A chronic state characterized of two or more seizures that were not provoked by specific events
  85. How do you confirm a seizure?
    • Through EEG recording
    • record a small cortical region, non-invasively
    • represent the aggregate signal of many thousands of neurons discharging simultaneously
  86. Ictal state
    Active seizure occurring
  87. How do you identify seizure foci?
    EEG recording, can identify even if patient is not having a seizure
  88. Interict state
    • EEG recording from an epilepsy patient not having a seizure
    • abnormal activity confined to seizure focus by "inhibitiory surround" which from spreading
  89. Sharp waves
    • Abnormal, unstable activity depicting where the seizure will originate from the cortex
    • can have sharp waves without having epilpesy that shows hyperactivity but not strong enough to produce a seizure
  90. What are the types of seizures?
    • Focal
    • Generalized  (primary, secondary, absence, tonic-clonic)
  91. Focal seizure
    • originatated from one hemisphere
    • associated with structural abnormality
    • depends on the region affected will determine symptoms
  92. Generalized seizure
    involved larger network of neurons across both hemispheres
  93. secondary generalization seizure
    focal seizure strong enough that is spreads throughout the brain to generalized seizures
  94. primary generalization seizure
    • initiate from all cortical areas simultaneously or origins to the thalamus
    • spike and wave activity 
    • instant return to normal activity
  95. Absence seizure
    • last a few secs
    • causes of loss of consciousness (spacing out)
    • can occur 100x per day
    • common in children 
    • don't have motor control
    • arise from thalamo-cortical networks excitibilitiy
  96. tonic-clonic seizure
    • have tonic muscle contraction causing clasping of extremities due to inhibitory-surround failing and causing intense activation of APs 
    • followed by clonic phase- repeated jerking and muscle contracts due to inhibitory circuit renengaging and oscillating 
    • end of clonic phase associated with flat voltage signal of EEG (postitcal suppression)
  97. Postitcal suppression
    end of clonic phase associated with flat voltage signal of EEG
  98. Status epileticus
    • a seizure lasting longer than 5 mins, requires termination of IV administration of diazepam (GABAaR agonist)
    • can be life-threatening
  99. Paroxysmal depolarizing shift (PDS)
    sudden, large long-lasting intracellular depolarization that trigger of train of APs at its peak
  100. What causes a PDS not go into a full blown seizure?
    • initial depolarization is mediated by AMPAR in fast ionotropic GluR. 
    • then due to circuitry, strong activity started to engage strong inhibitory interneurons (GABA) 
    • Hyperpolarize cells and prevent burst of activity from a full-blown seizure
  101. Feed foward inhibiton
    activated by neighboring cells
  102. Feedback inhibition
    Neuron itself activates inhibitory neurons
  103. What causes rhythmic rebound firing in the thalamic neurons?
    • T-type Ca+ channels: that are transiently activated by the strong hyperpolarization caused by Ca+ spike participating in rebound firing
    • several anticonvulsant drugs target T-type Ca channels
  104. What are the causes of causes of epilepsy ?
    • Genetic: TSC, channelopathies 
    • Symptomatic: environmental insult (head trauma, stroke, tumor, etc)
  105. Channelopathies
    • Mutation affecting excitation or hyperpolaricity of specific channels 
    • no two channelopathies are identical
    • diff combos of genetic channel variants will have distinct effect on neuronal firing
  106. Mutations associated with epilepsy affect inhibitory or excitiatory processes ? And how?
    • Inhibitory 
    • decrease GABA levels, release, response 
    • decrease excitiation of interneurons and migration
  107. What are the animal models for genetic epilepsy ?
    • 1. Spontaneous mut (CaV2.1) -> absence seizure 
    • 2. KO mice
    • 3. KI mice
    • 4. CKO that selectively delete candidate gene
  108. Scn1a (Nav1.1) channel
    Mutution associated with epilepsy 

    Na+ voltage-gated channels important for AP generation
  109. What happens with global deletion of Nav1.1?
    Cause seizure and premature death
  110. What happens with interneuron-specific deletion of Nav1.1
    Cause more severe seizures and premature deaths than global 

    specifically fast-spiking PV (basket cells) interneurons 
  111. Deleting excitiatory neuron-specific deletion of Scn1 causes...
    Does not cause seizure or effect
  112. Deletion of Scn1a from excitiory and inhibitory neurons...
    • Decrease seizures and mortality 
    • partially rescues phenotype -> suggest for a need of E/I balance

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Author:
aguzman93
ID:
320035
Filename:
MCB 165
Updated:
2016-05-12 10:25:29
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MCB
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Midterm 1
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