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- 1st antipsychotic drug
- D2R antagonist
- produces sedation, indifference to aversive stimuli; calms down Schizophernia, mania, and psychosis behaviors
- Physical disorder in the N.S.
- Physical basis that can be observed in the brain having surgical/ treatment
- degeneration and atrophy is visible
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
Understanding the fundamental basis of something
Patient-orientated, direct interaction w/ human subjects
Applies findings from basic science to clinical setting
How much of the disease can be attributed to a genetic factor
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)
- Single gene inheritance
- autosomal dominant or autosomal recessive
Multiple genes inheritance
Most psychiatric disorders are caused by
Multiple genetic factors that each alone increases susceptibility
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
What are the 3 types of validities for a disease model
- Construct validity
- Face validity
- predictive validity
Disease relevance of the methods by which a model is constructed
The model recapitulates important anatomical, biochemical, neuropathological or behavioral features of the human disease
The model responds to treatment in a way that predicts the effects of those treatments in humans
Cell culture (in vitro)
Immortalized cell lines, from embryonic mice
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
- 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
Disrupt an endogenous gene; cause loss of fxn mut.
- Express an exogenous gene
- 1. GFP: label cells and visiualzation
- 2. Cre recombinase: express specific cell types to manipulate
- Disrupt an endogenous gene in specific cell types
- Cre/ lox P system
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
Genome editing, Cas9
Recognizes and cleaves invasive DNA as part of the adaptive bacterial immune response
Serotonergic projections from
DAergic projections from
SNc (motor control) & VTA (reward/addiction)
The study of drugs specifically employed to affect the nervous system
- The concentration of a drug required to bind a given target
- Ki or IC50
- lower values = tighter binding, higher affinity
- 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
Combine affinity and efficacy
How selective the drug is for a particular target
- 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)
Molecular changes produced by a drug when it binds its target
Binds and activates a receptor but only has partial efficacy
Prevent/ blocks the action of an agonist
Binds to the same site of the agonist but has an opposite effect
What the drug does to the body, including intended and unintended effects
- What the body does with the drug
- absorption, distribution, metabolism, excretion
Diminish response to a drug
Enhanced drug effect
blood brain barrier
Prevents blood from getting into the brain, but can be problematic to get drug to brain
- 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
- Each NT has specific machinery for its synthesis, vesicle packaging, and reuptake/ degeratation
- many drugs modulate NT levels or receptors
Direct ligand-gated ion channels
7 transmembrane spanning domains; signal via 2nd messenger, slow synaptic transmission
Pentamer consisting of 2α, 2β, and 1γ subunits
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
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
- Restricted interest
- altered social communication
- altered react it to sensory stimuli
- resistance to change
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
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
Genetics of ASD
- monogenetic Syndromic disorder (FXS)
- De novo mut (not inherited)
- common variants of small effects combined will enhance or converge ASD
What are the synaptic fxns focused in ASD risk genes?
- Cell adhesion molecules
- scaffolding proteins
- signaling transduction proteins
- translational machinery
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
What are the environmental risk associated with ASD?
- Immune dysregulation -> can impact synaptic fxn
- maternal immune inactivation
See deficits in synaptic pruning in ASD
- During development, have sig overgrowth of of synaptic connections and then get pruned during plasticity to refine synaptic connections
- ASD failed to prune
What are the ways to model ASD in mice?
- Mutation in single gene
- mutation in chromosome region
- maternal immune challange
What are the mouse behaviors observed that have face validity to ASD?
- Ultraconic vocalization
- Reciprocal social interactions
- social approach
- repetitive behaviors
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
Affects both the brain and body, complex neurological and psychiatric problems
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"
examples of Syndromic disorders
- FXS (fmr1)
- Tuberous Sclerosis Complex (TSC 1/2)
- Down Syndrome (trisomy of chromosome 21)
- Rett Syndrome (MECP2)
- Angelman Syndome (UBE3A)
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
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
What are the genetic components of TSC?
- Tsc1 and Tsc2; two diff genes on separate chromosomes (loss of fxn)
- autosomal dominant, 100% penetrance
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
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
What are the clinical manifestion in neurological/ behavioral from TSC?
- mental retardation and learning difficulties
- sleep disorder
- austism and behavioral difficulties
- giant cell astrocytoma
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
What does TSC2 +/- (heterozygous mut) show?
It shows deficits in learning and memory, measured behavior in Morris water maze
TSC models affected in synaptic plasticity
- Learning deficits suggest to look at synaptic site of hippocampus
- Synaptic plasticity is altered
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)
What are the synaptic changes in TSC when testing LTD?
Loss of mGluR-LTD
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
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
What are the behavioral phenotypes in Tsc 1 +/- and Tsc2 +/-?
- Show reduced social interactions
- autistic phenotype
- model: social deficit monitored interaction of mice
What does cerebellum-specific KO of Tsc1 cause?
- Cause social abnormalities; recapitulate autistic behaviors
- social interaction ↓
- Reverse learning ↓
- grooming ↑
- stereotypies (communication) ↑
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
What are the known causes for epilepsy?
genetic disorder, infectious disease, traumatic brain injury, brain tumors, led poisoning
What are the risk associated with children with epilepsy ?
Learning disabilities, developmental day, and intellectual disability
- An acute abnormal, highly synchronous period of electrical activity in a restricted brain region
- last sec -> mins
- can happen once and never again
A chronic state characterized of two or more seizures that were not provoked by specific events
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
Active seizure occurring
How do you identify seizure foci?
EEG recording, can identify even if patient is not having a seizure
- EEG recording from an epilepsy patient not having a seizure
- abnormal activity confined to seizure focus by "inhibitiory surround" which from spreading
- 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
What are the types of seizures?
- Generalized (primary, secondary, absence, tonic-clonic)
- originatated from one hemisphere
- associated with structural abnormality
- depends on the region affected will determine symptoms
involved larger network of neurons across both hemispheres
secondary generalization seizure
focal seizure strong enough that is spreads throughout the brain to generalized seizures
primary generalization seizure
- initiate from all cortical areas simultaneously or origins to the thalamus
- spike and wave activity
- instant return to normal activity
- 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
- 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)
end of clonic phase associated with flat voltage signal of EEG
- a seizure lasting longer than 5 mins, requires termination of IV administration of diazepam (GABAaR agonist)
- can be life-threatening
Paroxysmal depolarizing shift (PDS)
sudden, large long-lasting intracellular depolarization that trigger of train of APs at its peak
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
Feed foward inhibiton
activated by neighboring cells
Neuron itself activates inhibitory neurons
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
What are the causes of causes of epilepsy ?
- Genetic: TSC, channelopathies
- Symptomatic: environmental insult (head trauma, stroke, tumor, etc)
- 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
Mutations associated with epilepsy affect inhibitory or excitiatory processes ? And how?
- decrease GABA levels, release, response
- decrease excitiation of interneurons and migration
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
Scn1a (Nav1.1) channel
Mutution associated with epilepsy
Na+ voltage-gated channels important for AP generation
What happens with global deletion of Nav1.1?
Cause seizure and premature death
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
Deleting excitiatory neuron-specific deletion of Scn1 causes...
Does not cause seizure or effect
Deletion of Scn1a from excitiory and inhibitory neurons...
- Decrease seizures and mortality
- partially rescues phenotype -> suggest for a need of E/I balance