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BISC 407 - Cellular and Molecular Neuroscience > Module IV - Lecture 3 - Schizophrenia > Flashcards

Module IV - Lecture 3 - Schizophrenia Flashcards

1
Q

What is the worldwide prevalence of schiziphrenia?

A

0.5-1%

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2
Q

Schizophrenia related symptoms account for how many hospitalizations?

A

30%

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3
Q

What percent of people with schizophrenia commit suicide?

A

5%

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4
Q

When is schizophrenia identified?

A

18-25 years of age

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5
Q

What are the negative symptoms of schizophrenia?

A

-flattened affect - reduction in emotinal expression
-avolition - decrease in motivation to perform self directed activities
-alogia - general poverty of speech

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6
Q

What are the positive symptoms of schizphrenia?

A

-disorganized speech - inability to formulate speech plan due to disruptions in cognitive functions like working memory
-auditory hallucination - hearing voices
-delusions - firm beliefs that are not realistic and not explaoined by the petients culture
-disorganized behavior - inaaprotpriate clothing social outbursts

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7
Q

What kind of disorder is schizophrenia?

A

psychotic spectrum disorder

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8
Q

What is schizophreniform disorder?

A

-the same symptoms as schizophrenia but they are present for at least 1 month but less than 6 months

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9
Q

What is needed to receive a schizophrenia diagnosis?

A

-two or more of the following symptoms for at least one month - hallucinations, delusions, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms
-impairment in one or more areas of function - social , occuptational, educational self care, for a significant period time since the onset of the illness
-continuous sign of the illness fr at least 6 months this can include prodromal or residual symptoms which are attenuated forms of the symptoms described

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10
Q

What is schizoaffective disorder? (mood disorder)

A

-a period of illness where the person had both psychotic symptoms needed for schizophrenia and either a major depression or manic episode
-the person experiences either delusions or hallucinations for at least 2 weeks when they are not having a depressive or mani episode
-the symptoms that meet criteria for depressive or manic episodes are present for over half of the illness duration

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11
Q

What is delusional disorder?

A

-presence of delusion for at least a month
-the person has never met criteria for schizophrenia
-the persons function is not impaired outside that specific impact of the delusion

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12
Q

What is brief psychotic disorder? (very brief schizo episdoes)

A

one or more of the following symptoms are present for at least 1 day or less than 1 month - delusions, hallucinations, disorganized speech, grossly disordered or catatonic behavior

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13
Q

What is attenuated psychotic disorder? (very mild like schizo like symptoms)

A

-one or more of the following symptoms in an attenuated form - delusion, hallucinations, or disorganized speech
-symptoms need to occur once a week for the past month and must have started or gotten worse in the past year
-symptoms cause distress and disable the individual or to suggest to others that the person needs clinical help
-person has never met diagnostic criteria for a psychotic disorder and the symptoms are not better attributed to another disorder or substance use or to a medical condition

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14
Q

What is the concordance rate of schizophrenia?

A

-genetic component - monozygotic twin (48% likelihood) have pretty similar genes and this is not 100% so genetic component is present and an environmental factor that contributes to development of schizophrenia
-what environmental factors causes the disorder so have genetic predisposition but event in environment pushesyou over the edges and get the disorder like a life stressor

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15
Q

Even though the dopamine theory is no longer considered, what is the dopamine theory of schizophrenia?

A

-the potency of first generation antipsychotic drugs in treating positive symptoms is correlated with the ability to block D2 dopamine receptors
-rather affects serotonin functions more

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16
Q

What is the glutamate hypothesis of schizophrenia?

A

phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor but exacerabte both cognitive impairment and psychosis in patients with schizophrenia

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17
Q

What is ketamine sufficient to produce?

A

schizolike psychosis in individuals with schizphrenia

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18
Q

What does the hypofucntion of NMDA receptors state?

A

NMDA receptors on GABAergic interneuons lead to diminished inhibtiory influences on neuronal function contributed to schizophrenia and causing an increase in excitation

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19
Q

Elevated glutamatergic neurotransmission in what region of the brain is consistently observed in humans with schizophrenia?

A

hippocampus

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20
Q

Where do neurons that leave the hippocampus from the CA1 and subuculum project to?

A

they send glutamatergic neurons to the NAc

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21
Q

Where do neurons from the NAc sent GABAergic projections too?

A

the ventral pallidum

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22
Q

Where do neurons in the Ventral pallidum send GABAergic projections to?

A

the VTA

23
Q

Where does the VTA send a dopaminergic projection to?

A

the NAc

24
Q

How does the glutamate hypothesis affect the transmission from the hippocampus?

A

since you get less glutamate from the hippocampus to the NAc there is less inhibition of the NAc on the ventral pallidum causig more inhibition form the ventral pallidum to the VTA causing the VTA to release less dopamine on the NAc

25
Q

What is the issue with the proteins in schizophrenia?

A

issue with glutamatergic postsynaptic proteins

26
Q

What are some of the gene mutations implicated in schizophrenia?

A

GRIA3, TRIO, CACNA1G

27
Q

What is the 3q29 mutation locus?

A

deletion in these 29 genes causes the highest likelihood of getting schizophrenia and in a preclinical mouse model it was found that deletion in 6 genes causes a reduction in protein expression

28
Q

What other deletion can cause schizophrenia?

A

2p16.3 NRXN1 del can cause schizophrenia

29
Q

What are the DLG1 or SAP97 mutations involved with schizophrenia clustered?

A

they are clustered in the PDZ2 binding domain

30
Q

In what protein family is SAP-97?

A

the same family as PSD-95
-this is known as a MUGUK protein family

31
Q

What do MUGUK protein families do; how do we know this?

A

support glutamatergic synapse function
-KO these proteins get a reduction in AMPA and NMDA currents beacuse there are less receptors because there is nothing to hold these receptors and by nothing i mean proteins

32
Q

Does SAP97 regulate glutamatergic synapse function in CA1 neurons; how do we know this?

A

no because if we get rid of sap97 in CA1 neuron glutamatergic synapse function is unchanged because there are schaffer collateral glutamatergic nueorns between CA1 and CA3

33
Q

Dysfunction in what region of the brain is actually related to schizophrenia?

A

dentate gyral dysfunction - especially in the granule neurons in the DG - these synapses come from the entorhinal cortex and project to CA3 pyramidal neurons

34
Q

Where is SAP97 found?

A

in the cell bodies of pyramidal CA1 neurons but not in the dendrites of these neurons but the DG neurons are full of SAP97

35
Q

What does the reduction of the expression of SAP97 in DG neurons cause?

A

an increase in synaptic AMPA currents aka four fold change and NMDA current increase slightly but not a significant amount and SAP97 sits in the extra synaptic regions and holds the pool of AMPA receptors outside of the synapse and get rid of the ampa receptors are away from the synapse and can diffuse into it

36
Q

Where is SAP97 found and what does it do?

A

it sits in extrasynaptic areas and it holds the AMPARs reserve pool preventing ampars from diffusing into the synaptic cleft

37
Q

What does SAP97 PDZ2 domain bind to?

A

the c terminal of the pdz binding domain of GluA1
-it is the only muGUK protein that can bind directly to AMPA receptors because psd95 binds to it through the axuiliary protein knwon as TARP but SAP97 can bind directly because GluA1 has a PDZ binding domain on its c terminal tail which can bind to the PDZ2 binding domain of SAP97

38
Q

What does the GluA1-delta7 replacement cause where you remove the c terminal pdz binding domain of the protein?

A

causes an augmentation in synaptic strength in dentate granule neurons but not in CA1 neuorns (there is a slight increase in AMPA currents but not much because SAP97 is inly found in the cell bodies of these neurons not in the dendrites so not significant increase)

39
Q

What augments synaptic transmission in DG granule neurons?

A

schizophrenia missense mutations in SAP97

40
Q

What does inhibition of SAP97 function in the DG compared to CA1 neurons of the hippocampus produce deficits in?

A

it causes deficits in contextual information processing = via an object and context paradigm in rats by putting rats with an object in a certain environment until they associate the environment with that object and then add another object to the environment the rats will pay attention more to the other object out of context but take out SAP97 in the DG this does not happen

41
Q

What deficits are observed in schizophrenia?

A

deficits in pattern separation

42
Q

What is pattern separation and what is pattern completion?

A

separation - distinct but overlapping or highly similar patterns of neuronal inputs are transformed into more distinct neuronal representations
completion - a full memory representation is reconstructed from a similar representation of partially overlapping inputs

43
Q

What can increased firing in the dentate granule neurons cause?

A

disrupts the pattern separation function if the DG causing hyperassociation

44
Q

What does the hyperassociative hippocampal memory system give rise to?

A

inappropriate associations, distorted perception, irrational expectations and hallucinations

45
Q

How do things that should not go together become associated in the schizophrenic brain leasing to delusional thinking?

A

more firing - more neurons firing together ad wiring together more LTP
-more LTP means more association are being made in the external world than would be considered normal leading to this delusional thinking

46
Q

In what other brain regions does increased firing in the dentate granule neurons cause aberrant activity leading to a number of schizophrenia related phenotypes and what are these phenotypes?

A

DG - pattern separation
Amygdala - mood
Hippocampus - memory
VTA/SN - reward

47
Q

What is accelerated in adolescent schizophrenia and what is this due to?

A

gray matter loss due to not neurons dying but due to reducntion in neurpil which is the axons dendrites and synapses and synpases take the most ampount of space in the brain and when you lose these synapses there is hyperpruning of them in adolescence in the schizophrenic brain

48
Q

In what regions of the brain is gray matter loss observed in schizophrenia and what function do they each affect?

A

dorsolateral prefrontal cortex - working memory
-superior temporal cortex - speech and auditory processing
-amygdala - emotional response
-hippocampus - explicit memory

49
Q

What happens to the spine density in schizophrenia?

A

there is decreased dendritic spine density

50
Q

Where do fewer spines and glutamatergic synapses in patients with schizophrenia arise from and how did they find this?

A

it may come from a homeostatic control mechanism that works to correct and counteract aberrantly elevated glutamatergic NT in the brain due to mutations in PDZ2 binding domain of SAP97;
put in channelrhosopdin and flashed a light so they fire at high rate for 6 days and after 6 days the number of synapses reduce because the firing and excitation rate of a neuron is hardwired

51
Q

What happens synapse wise in a normal patient compared to a schizophrenic patient?

A

entorhinal cortical neurons synapse onto DG1 neuorn and DG2 neurons which have two similar stimuli but not the same thing
-in early schizphrenia there is rise in glutamatergic synapses and this causes a hyperactive network which causes these two stimuli to form synapses on both the DG1 and DG2 neurons
-in prodromal form of disease there is homeostatic mechanism to control this but get the wrong pruning do have wrong associations

52
Q

What may increase synaptic pruning in schizophrenia?

A

elevated C4 expression which is similar to C3 and this is secreted by astrocytes which is cleaved by the c1 complex on neurons to make ic3b which goes and binds to inactive neurons and the CR3 receptor on microglia can bind to it and cause these inactive synapses to be eaten up

53
Q

Does compromising the function of these other schizophrenia linked genes like Trio and GRIN2A produce abberant increase in synaptic strength in the DG?

A

want to know in future is we see similar synaptic pathology when it comes to evaluating the genetics of the disease

54
Q
A

BISC 407 - Cellular and Molecular Neuroscience (23 decks)

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