Deck 11: Brain Disorders

Question 1

The text lists three treatments for Parkinson's disease: l-dopa administration, deep brain stimulation, and cell-replacement therapy. Choose one of these and discuss the theory behind how it works and the limitations of its success and effectiveness.

Answer 1

l-dopa is the precursor to dopamine. Dopamine does not cross the blood-brain barrier so patients are given l-dopa, which does cross the blood brain barrier. Since Parkinson's disease appears to be a loss of dopaminergic input to the striatum, increasing dopamine levels should help compensate for the dopaminergic loss. This treatment has been fairly successful in treating the disease. One of the side effects is levodopa-induced dyskinesia. In addition, the effects of l-dopa decrease over time so it is only effective for a few years.
Deep brain stimulation: Deep brain stimulation is used for many diseases. The theory behind it for Parkinson's is that the basal ganglia circuitry is not functioning correctly and so areas of the brain are stimulated to compensate for the increased activity in GPi/SNr. Although it is not known how DBS works, it is thought to inhibit the output of the STN, which would reduce the excitation to the GPi/SNr and decrease the inhibition of the brainstem circuits. DBS has been quite successful, however it does require invasive brain surgery to implant electrodes.
Cell-replacement therapy: The idea behind cell-replacement therapy is to replace dying dopaminergic neurons. To do this embryonic stem cells are implanted into the striatum and there they release dopamine. There are many limitations to this therapy; the stem cells must survive and must release dopamine. In addition, a large number of dopaminergic neurons are required to be effective and there is often contamination from other cell types. This therapy also requires patients to be put on immunosuppressants to reduce the likelihood of rejection of the cells.

Question 2

If α-synuclein knock-out mice and mice with normal α-synuclein were injected with α-synuclein in the substantia nigra, which mice would develop symptoms of Parkinson's disease and why?
(a) The wild type mice would develop symptoms of Parkinson's as the α-synuclein would be able to cause mitochondrial dysfunction in the substantia nigra.
(b) The α-synuclein knock-out mice would develop symptoms of Parkinson's as the α-synuclein would be able to cause mitochondrial dysfunction in the substantia nigra.
(c) The α-synuclein knock-out mice would develop symptoms of Parkinson's because the α-synuclein protein would aggregate and spread cell to cell.
(d) The α-synuclein wild type mice would develop symptoms of Parkinson's because the injected α-synuclein protein would recruit native α-synuclein and the aggregates could spread cell to cell.

Answer 2

(D)
α-synuclein acts like prion proteins (PrPs) in prion disease in which the infectious protein recruits the native protein to become maladaptive and to spread. In Parkinson's this spread of α-synuclein is linked to symptoms of the disease.

Question 3

It has been difficult to develop drugs for brain disorders including AD. For example, many groups have tried to target γ-secretase.
A. Why is γ-secretase a good target for Alzheimer's treatment?
B. What is one reason, so far, that drugs targeting γ-secretase have not been successful?

Answer 3

γ-secretase is the enzyme that produces the Aβ peptide after APP-β has been cleaved from the APP peptide. This includes Aβ₄₀ and Aβ₄₂, peptides that aggregate to form plaques in Alzheimer's. If this enzyme could be altered it could reduce the production of Aβ₄₂, which would reduce the potential for aggregates to form and slow the progression of the disease.
B. There are many side effects to the drugs probably because γ-secretase targets many proteins other than APP and so the drugs have very broad and damaging effects.

Question 4

What is the link between Down syndrome and familial Alzheimer's disease?
(a) The APP gene is located on Chromosome 21, which has an extra copy in Down syndrome.
(b) The APP gene is located on Chromosome 14, which is the duplicated chromosome in Down syndrome.
(c) The presenilin 1 and 2 gene is located on Chromosome 21, which is the duplicated chromosome in Down syndrome.
(d) The presenilin 1 and 2 gene is located on Chromosome 14, which is the duplicated chromosome in Down syndrome.

Question 5

Which is NOT an example of a disease involving prions? Select all that apply.
(a) Kuru
(b) Creutzfeldt-Jakob disease
(c) Scrapie
(d) Huntington's disease
(e) Amyotrophic lateral sclerosis

Question 6

In patients with Parkinson's disease, neurons in the SNc die. Based on the basic circuitry in Figure Q11-13, why does the absence of these neurons result in excessive activation of the inhibitory output neurons in the GPi/SNr? Figure Q11-13

Question 7

What is the main pathological feature of prion diseases?
(a) Death of cells in the substantia nigra
(b) Spongiform encephalitis
(c) Amyloid plaques
(d) Neurofibrillary tangles
(e) The presence of Lewy bodies
(f) Overexpression of presenilin

Question 8

What does this tell you about the relation between these two gene products?
(a) They are in independent pathways.
(b) Parkin is downstream of Pink1.
(c) Pink1 is downstream of Parkin.
(d) Both gene products act on a common target.

Question 9

What is ApoE? Select all that apply.
(a) A component of high-density lipoproteins
(b) A molecule involved in lipid transport
(c) A molecule that binds to Aβ
(d) A molecule that triggers the accumulation of the tau protein
(e) A molecule that triggers microglia accumulation
(f) A molecule that is part of the γ-secretase complex

Question 10

What are two pathological features of patients with Alzheimer's disease?
(a) Death of cells in the substantia nigra
(b) Spongiform encephalitis
(c) Amyloid plaques
(d) Neurofibrillary tangles
(e) The presence of Lewy bodies
(f) Overexpression of presenilin

Question 11

There are many neurodegenerative diseases with many symptoms. List two common themes with these different diseases and two properties that make each disease unique.
Psychiatric Disorders

Question 12

Figure Q11-9 shows several molecules that have been targeted for Alzheimer's therapy. Explain the rational for targeting each molecule: Figure Q11-9
A. α-secretase
B. Microglia
C. ApoE

Question 13

Pink1 and Parkin mutant flies both die prematurely, have degeneration of dopamine neurons, and have mitochondria with abnormal morphology and function. What happened when Parkin was overexpressed in Pink1 mutant flies?
(a) They still died, but their dopamine neurons were not degenerated.
(b) The defects appeared earlier and so the Drosophila died even younger.
(c) The Parkin flies were rescued.
(d) There was no change.

Question 14

What are presenilins?
(a) Proteins that aggregate in amyloid plaques
(b) Proteins that aggregate in neurofibrillary tangles
(c) Proteins that are part of the γ-secretase complex
(d) One of the cleaved proteins from APP

Question 15

How does Figure Q11-2 contribute to the evidence that the Aβ oligomer interferes with loss of memory in Alzheimer's disease? Figure Q11-2
(a) The experiment showed that the Aβ oligomer induced long-term depression, suggesting it could reduce learning and memory.
(b) The experiment showed that the Aβ oligomer blocked synaptic transmission, suggesting it could block memory formation.
(c) The experiment showed that the Aβ oligomer blocked memory formation while keeping learning intact.
(d) The experiment showed that the Aβ oligomer blocked long-term potentiation suggesting that it could block learning and memory.

Question 16

In the 1990s, drug users started developing Parkinson's like symptoms. It was found that a contaminant, called MPTP, was in an opioid-like drug. How does MPTP cause Parkinson's like symptoms?
(a) MPP⁺ inhibits mitochondrial function in dopaminergic neurons.
(b) MPTP inhibits mitochondrial function in dopaminergic neurons.
(c) MPTP increases the enzymatic activity of monoamine oxidase with increases the number of free radicals in dopaminergic neurons.
(d) MPP⁺ blocks the release in dopamine from dopaminergic neurons, specifically from the substantia nigra.

Question 17

Both Prp^+/+ and Prp^-/- mice were inoculated intracerebrally with prions. Which mice developed symptoms of prion disease and why?

Question 18

List three pieces of evidence that Aβ production contributes to Alzheimer's disease?

Question 19

How is the Aβ protein produced? Include the name of the precursor protein.
(a) The APP protein is cleaved by α-secretase, which is then cleaved by β-secretase.
(b) The APP protein is cleaved by β-secretase and then by α-secretase.
(c) The APP protein is cleaved by α-secretase and then γ-secretase.
(d) The APP protein is cleaved by β-secretase and then γ-secretase.

Question 20

Why is Rett syndrome found only in human females?
(a) It is a recessive mutation located on the X chromosome and two copies are required to show the disease.
(b) It is a dominant mutation on the X chromosome and you need both copies of the mutation to show the disease.
(c) It is caused by a loss-of-function mutation of MeCP2 that is only expressed in females because it is silenced in males.
(d) It is caused by a loss-of-function mutation of MeCP2, and X-linked gene, and when this is silenced in males, they often die prenatally or as infants.

Question 21

Why has it been difficult to develop effective drugs for psychiatric disorders?
Neurodevelopmental Disorders

Question 22

What is the difference between barbiturates and benzodiazepines?
(a) Barbiturates act on NMDA receptors and benzodiazepines act on GABA_A receptors.
(b) Barbiturates act on GABA_B receptors and benzodiazepines act on GABA_A receptors.
(c) Barbiturates can independently activate GABA_A receptors whereas benzodiazepines augment the action of intrinsic GABA.
(d) Barbiturates block NMDA receptors whereas benzodiazepines activate GABA receptors.

Question 23

Mecp2 was knocked out only in GABAergic neurons. What do the results shown in Figure Q11-37 suggest about the actions of MeCP2? Figure Q11-37

Question 24

To better understand how MeCP2 regulates neuronal function, a mouse model was generated in which the Mecp2 gene was knocked out. The abnormal phenotype of this mouse could be rescued by conditional expression of MeCP2 in young mice. Why is this an important finding? Select all that apply.
(a) It shows that the defects seen in the mice are due to the dysfunction of MeCP2.
(b) It shows that Rett syndrome is due to a dysfunctional Mecp2 gene.
(c) It shows that Mecp2 is expressed in all neurons.
(d) It indicates that the symptoms are reversible and therefore the disease can be treated by restoring MeCP2.

Question 25

Most current anti-depressants are SSRIs. What is the result of SSRI action? Select all that apply.
(a) Increase the reuptake of serotonin into presynaptic vesicles through VMATs
(b) Increase the reuptake of serotonin into the presynaptic terminal through PMT
(c) Increase in amount of serotonin in the synaptic cleft
(d) Increase in the amount of monoamines in neurons

Question 26

Patients taking reserpine also experience symptoms of which disease?
(a) Alzheimer's disease
(b) Amyotrophic lateral sclerosis
(c) Huntington's disease
(d) Parkinson's disease

Question 27

What is one cellular/molecular basis for dopamine action on VTA leading to addiction?
(a) Increases the AMPA/NMDA receptor ratio on VTA dopamine neurons
(b) Increases the Ca²⁺ current on VTA neurons
(c) Closes potassium channels and therefore enhances conduction velocity in VTA neurons
(d) Decreases the GABA receptor current on VTA neurons

Question 28

In Figure Q11-39, if you were to conditionally restore MeCP2 protein to a MeCP2 knockout mouse at week 10, through removing a lox-stop allele with an inducible excision, how do you predict that would change the percent surviving animals? Justify your answer. Figure Q11-39
(a) It would increase at week 10.
(b) It would remain the same at week 10.
(c) It would continue to decrease but at a slower rate.
(d) It would decrease even faster.

Question 29

Activation of type 1 mGluRs induces LTD through protein translation. What do you predict would happen to LTD if you could selectively increase PP2A phosphatase that regulates FMRP phosphorylation?
(a) mGluR activation would result in FMRP phosphorylation and repression of protein translation. This would enhance LTD.
(b) mGluR activation would result in FMRP dephosphorylation and repression of protein translation. This would decrease LTD.
(c) mGluR activation would result in an increase in phosphorylated FMRP which would increase repression of protein translation. This would decrease LTD.
(d) mGluR activation would result in an increase in dephosphorylated FMRP which would decrease repression of protein synthesis. This would enhance LTD.

Question 30

Benzodiazepines help reduce anxiety but they also cause sedation. A more effective drug would reduce anxiety without causing sedation. The experiment shown in Figure Q11-28 was performed in which the histidine was replaced by an arginine on either the α1 or α2 subunit of GABA_A receptors. This substitution causes the subunit to become insensitive to benzodiazepines while retaining its sensitivity to GABA. Figure Q11-28
A. What happened to the α1(H101R) mice when they were given diazepam and what conclusion can be drawn about the α1 subunit?
B. What happened to the α2(H101R) mice when they were given diazepam and what conclusion can be drawn about the α2 subunit?
C. What does this tell you about designing a drug for anxiety?

Question 31

Figure Q11-29 illustrates how many drugs of abuse enhance dopamine action on its postsynaptic targets, specifically the nucleus accumbens and prefrontal cortex. Figure Q11-29
A. What are two mechanisms nicotine uses that result in increased dopamine release on its postsynaptic targets?
B. How does cocaine increase dopamine in the postsynaptic targets of VTA dopaminergic neurons?
C. How do cannabinoids increase dopamine in the postsynaptic targets of VTA dopaminergic neurons?

Question 32

You have discovered a potential new drug to treat schizophrenia that binds competitively to the dopamine D2 receptor. You perform a competitive binding assay to test the effectiveness of the drug action. What is the idea behind the assay and what result would give you a high affinity drug-receptor binding?

Question 33

What evidence is there for systems other than dopaminergic systems that are altered in schizophrenia?

Question 34

Reserpine is used to treat schizophrenia and it acts by blocking vesicular monoamine transporters (VMATs). Where does reserpine act in neurons and what happens to these neurotransmitters when the neurons are exposed to reserpine?

Question 35

Reserpine is used to treat schizophrenia and it acts by blocking vesicular monoamine transporters (VMATs). Which neurotransmitter systems are influenced by reserpine? Select all that apply.
(a) Serotonin
(b) Dopamine
(c) Acetylcholine
(d) GABA
(e) Norepinephrine
(f) Glutamate

Question 36

In thinking about finding a treatment for ID, Rho-GTPases might be a target for therapeutic drugs. In general, why is this problematic?

Question 37

One protein implicated in intellectual disability (ID) is oligophrenin. How does this protein influence neurons during development? Choose all that apply.
(a) Enhances Rho-GTP levels
(b) Decreases spine length
(c) Impairs synaptic transmission
(d) Enhances Rho-GTPase activity

Question 38

Rett syndrome is caused by mutation in an X-linked gene called MeCP2. Why does mutation of this one gene cause so many neurological defects?
(a) CeCP2 regulates protein synthesis by global phosphorylation of protein kinases.
(b) CeCP2 causes irregular protein folding in a ubiquitous neural protein.
(c) CeCP2 binds to methylated DNA and regulates gene expression.
(d) CeCP2 is a histone that controls epigenetic regulation of gene expression.

Question 39

An experiment discussed in Chapter 10 and shown in Figure Q11-31 shows in vivo single unit recordings from VTA dopaminergic neurons in a monkey trained to associate a light with a reward, juice. How does the enhancement of dopamine action of VTA neurons lead to addiction if the dopamine VTA pathway normally signals reward prediction errors? What is the pathway involved and what happens in addiction? Figure Q11-31

Question 40

Many neurodevelopmental disorders are associated with alternations in synaptic function. Why would alterations in synaptic function during development result in long-term changes in synaptic circuitry and behavioral deficiencies??