Exam Slides Flashcards
1
Q
4 symptoms of SCH
A
- Delusions
- Hallucinations
- Disorganized speech
- Alterations in executive functions
2
Q
The age of onset of SCH coincides with what?
A
The maturation of the PFC
3
Q
What is the cause of SCH
A
Unknown
4
Q
What are the 4 main hypotheses of SCH
A
- Neurodevelopmental
- Dopamine
- Hypofrontality
- Glutamate
5
Q
What is the environmental model of SCH
A
Suggests that the late onset is caused by the increased cognitive and social demands of that stage of life
6
Q
What are the genetic models of SCH
A
Suggests that there could be a genetic basis, and that genes may interact with the environment
7
Q
What is the neurodevelopmental model of SCH
A
Suggests that disrupted/abnormal brain development could cause SCH and it only becomes apparent later when those brain areas are needed/matured
8
Q
Heterogeneity genetic contribution to SCH
A
It is separate distinct diseases, each inherited based on specific gene mutations
9
Q
Monogenetic genetic contribution to SCH
A
A dominant single gene mutation resulting in highly variable phenotypic expression
10
Q
Polygenetic genetic contribution to SCH
A
The phenotype is caused by multiple gene mutations
11
Q
Combinatorial model of genetic contribution to SCH
A
It results from complex interactions between genetic susceptibility and environment
12
Q
What receptor is thought to be involved in SCH
A
D2 receptor
13
Q
What is the issue with the D2 receptor in SCH
A
it is overactive
14
Q
What is the evidence that supports the dopamine hypothesis of SCH
A
D2 receptor agonists are effective in the treatment of some people with SCH
15
Q
What is the neurodevelopmental hypothesis of SCH
A
Brain abnormality present at or shortly after birth is “unmasked” as a result of normal maturation events that occur in late adolescence and early adulthood
16
Q
What are the 7 stages of neurodevelopment
A
- Neurogenesis
- Migration
- Growth of axons
- Synaptogenesis
- Synaptic pruning
- Neuronal death
- Myelination
17
Q
Emergence of SCH symptoms correlate with the stage of development occupied by significant __________
A
synaptic pruning
18
Q
Abnormalities to what gene has been associate with the symptomology of SCH
A
DISC-1
19
Q
The DISC-1 gene is involved in what brain process?
A
Glutamate
–> Neurotransmission and plasticity
20
Q
What brain region is DISC very active in?
A
Forebrain
21
Q
DISC-1 is highly expressed in areas where there is what?
A
Neurogenesis
22
Q
DISC-1 interacts with many proteins and plays a role in (3)
A
- Neuroplasticity
- Axon growth
- Neural migration
23
Q
In SCH there is an issue with ________ and a lower number of ________
A
Synaptic elimination
Dendritic spines
24
Q
SCH is considered a disorder of _______
A
cortical connectivity
25
What are the 2 types of imaging to detect SCH
Diffusion tensor imaging and fMRI
26
What brain region seems most affected in SCH
Frontal lobe
27
Stage 1: Presymptomatic SCH
<15 y
| The negative symptoms start
28
Stage 2: Prodrome SCH
15-18y
| Cognitive and social deficits
29
Stage 3: Psychosis SCH
18-25 y
| Diagnosis and start to see positive symptoms
30
Stage 4: Chronic illness SCH
>25y
| Positive and negative symptoms, start to seek treatment
31
What are the 3 types of treatment for chronic SCH
Medical
Psychological therapy
Rehabilitation
32
During stage 3 of SCH, what starts to be seen in the brain in terms of grey matter
Deficient myelination and excessive excitatory pruning
33
There is decreased white matter in what brain regions in SCH
Frontal lobe
Cerebellum
Limbic structures
34
What NT are altered in SCH
Dopamine
Serotonin
Glutamate
35
There are brain abnormalities in what 2 brain regions in SCH
PFC
| Hippocampus
36
3 brain pathology in SCH
1. Lateral ventricle enlarged
2. Reduced brain volume (particularly grey matter)
3. Abnormal/reduced neuronal complexity
37
Abnormal neurodevelopment results in _______ dopamine activity in the _______ in SCH
excessive
| limbic system
38
Abnormal neurodevelopment results in ________ activation within the ______ in SCH
Reduced
| Prefrontal cortex
39
What are the 3 things that result from hypofrontality in SCH
1. Lower frontal lobe activity
2. Reduces axon density in the PFC
3. Reduced dopamine in the PFC
40
Abnormal limbic system = _______ symptoms SCH
positive
41
Abnormal PFC = _______ symptoms in SCH
negative
42
What type of life events have been correlated with the onset of SCH
stressful
43
What happens to a person with SCH when they get stressed
Their symptoms get worse
44
Stress response mechanisms appear to be ______ in some people with SCH
abnormal
45
What are the 2 types of medication for treating SCH
Typical and atypical antipsychotics
46
What is the main atypical antipsychotic
Clozapine
47
What is Clozapine reserved for?
Patients with treatment resilience
48
Why isn't Clozepine used more often in people with SCH
It has sever side effects like agranulocytosis and seizures
49
Agranulocytosis
lower production of white blood cells
50
Without medication, schizophrenics relapse at a rate of _____ within the first year of diagnosis
60-70%
51
Damage to what area of the brain has been shown to have masked effects of depression until 2 y in monkeys
Dorsolateral prefrontal cortex
52
What is the cause of mood disorders?
Unknown
| Thought to maybe be affected by biological, psychological and social factors
53
What are the 2 main types of depression
```
Major depressive disorder
Bipolar disorder (depression and mania)
```
54
What is the prevalence of depression in women compared to men?
Women are 2x as likely
55
What is the most common type of mood disorder
depression
56
What are the 2 major types of mood disorders
Depression
| Mania
57
Diagnosis of depression depends on what two things?
Symptoms and the duration of the symptoms
58
What is diagnosis of depression often based on?
Self report
59
What demographic is most likely to get depression
Women of child-bearing years
60
Major depression:
Exhibit episodes of depressed mood for 2+ years
61
what is a major physiological disturbance of major depression
sleep problems
62
What characterizes bipolar disorder
the presence of one or more manic episodes
63
The exact consequence of maternal depression on the child depends on what
the specific stage of development that the disruptions occured in
64
Children of depressed mothers often show these 6 characteristics
1. More drowsy or fussy
2. Less relaxed or content
3. Engage in less toy exploration
4. Less focused play
5. Rated as crying more, difficult to sooth
6. Higher rates of psychiatric illness at school age
65
What 3 factors might cause the effects of maternal depression on the child
1. Genetics
2. Prenatal environment
3. Parenting style/home environment
66
Prenatal stage effects of maternal depression (4)
- Poor nutrition
- Inadequate prenatal care (not taking vitamins)
- higher preterm birth and low birth weight
- higher incidence of spontaneous abortion
67
Maternal depression effects/symptoms of infants (3)
- Anger and protective style of coping
- Passivity and problems with attention
- Lower cognitive performance compared to peers
68
The effects on toddlers with depressed mothers (2)
- Less mature expression of autonomy and lower peer interactions
- Cognitive: less creative play and lower cognitive performance
69
Developmental effects of adolescents with depressed mothers (4)
- Difficulty adapting to new situations
- Affective disorders, anxiety, conduct disorders and panic disorders
- ADHD and learning disorders ***
- Higher incidence of substance abuse and alcohol dependence
70
What is the genetics of depression
There has been no clear link found
71
What is the current focus in research on genes in childhood depression
Trying to see what depression looks like in children and find potential risk factors
72
Epigenetic effects of a depressed mother
Could inherit an abnormal stress response
Mother's depressive behaviours can train the child's brain to act in a certain way to a stressor
73
What is the controversy in diagnosing depression in children
Do not want to label them that young
74
What medical treatment for depression works in adults but not in children or adolescence
Tricyclic anti-depressants (TCA)
75
What drug treatment is more effective with some children and adolescents with depression
SSRIs
76
What is the main SSRI drug
Fluoxetine
77
Other than affect serotinin, what do SSRIs do?
They can induce epigenetic factors (increase neuroplasticity)
78
Differences in action of SSRI verses TCA could provide clues on _________ pathogenesis of depression
early-onset
79
How do TCAs and SSRIs increase NT
block reuptake
80
How do MAOIs increase NT
inhibit breakdown
81
What techniques is used to study sleep?
EEG --> monitors brain waves
82
What are the 5 sleep alterations in depressed children and adolescents
- Sleep continuity disturbance
- Reduced time until REM stage
- Increased time spent in REM stage
- Decreased delta waves (stage 3 and 4 sleep)
- Difficulty waking up
83
Paroxetine (Paxil) is what type of drug
Anti-depressant
84
Why are TACs not used in children and adolescents
They are not very effective
| They can cause severe side effects (even death)
85
There are higher levels of what in adults with depression
Cortisol during the day and night
86
About __% of depressed adults show hyper cortisol secretion
50`
87
Do depressed children show excess cortisol
Not usually
88
In depressed adults and children there is decreased volume of _____ and decreased volume of _____ only in adults
Amygdala
| Hippocampus
89
What are the 4 neurological characteristics associated with depressed adults
1. Excess cortisol
2. Reduced size of frontal lobe and amygdala
3. Hippocampal atrophy
4. Abnormality in orbitofronal cortex linked to early onset
90
Abnormality in what brain region has been linked with early onset of depression? What does this result in?
Orbitofrontal cortex
| > Abnormal serotonergic function
91
What is used to test white matter abnormality?
Diffusion tensor imaging
92
What is DTI used for
It evaluates the integrit of white matter tracts
| >Specifically subcortico structures
93
DTI has shown what is depressed in individuals
Abnormality in the corpus callosum
94
What gene is implicated in SCH that might also be implicated in bipolar disorder
EGR3
95
What CNS protein does EGR3 affect?
BDNF
96
Lower EGR3 leads to _____ BDNF
reduced
97
What is the direction of the relationship between EGR3 and BDNF
Bi-directional
| They affect each other
98
What are the brain effects of reduced EGR3? (2)
1. Impaired neuroplasticity and resilience
| 2. Increased vulnerability to stress
99
Prevalence of down syndrome
1 in 1000
100
What are the 2 gender differences in DS
1. More in males
| 2. Higher infant mortality in females
101
What is the first prenatal test for DS? Then what happens?
```
Nuchal translucency (ultra sound)
>> If it indicates DS then other tests like karyotyping are performed
```
102
What does karyotyping test/
The number and structure of chromosomes
103
Probability of infant having DS increases with mother's ___
age
| >>But this is going down
104
Aneuploidy =
abnormal number of chromosomes
105
What is the problem with aneuploidy in DS?
There is an "over-expression" of many genes and proteins
106
What are the 2 types of aneuploidy in DS, what are the prevalences
```
Complete trisomy (95%)
Mosaic or partical trisomies (5%)
```
107
What are the 2 hypotheses for DS
1. Gene dosage effect hypothesis
| 2. Amplified developmental instability hypothesis
108
What is the gene dosage effect hypothesis
The extra distal genes on the 21st chromosome (DSCR genes) that are present in DS are important for regulating neurodevelopment. The presence of the extra genes can disrupt development and cause specific DS phenotypic traits
109
The severity of DS according to the gene dosage effect depends on what?
The extent of trisomy in the DSCR
110
What is the amplified developmental instability hypothesis
- DS phenotypes result from the elevated activity of specific genes (DSCR) that result in the over production of DSCR proteins, which in turn cause global disruption of protein homeostasis
>Causes pervasive developmental instability/ abnormality
111
Full trisomy =
Complete extra chromosome
112
Partial trisomy =
One part of chromosome 21 moves to another chromosome
113
Mosaicism -
Still see trisomy 21, but only in some cells
| >> Error in cell division after fertilization
114
What are the cognitive abilities with ppl with Mosaicism DS
They have higher mean cognitive scores than those with full trisomy
115
How could XIST, the X-inactivation gene, be potentially used to treat DS?
XIST activation produces RNA that coats the surface of the chromosome 21.
--> Blocks genes on the extra chromosome 21 from being accesses and thus suppresses expression
116
When would XIST have to be given to be an effective treatment for DS?
Early in development to try to normalize the expression of genes
117
Brushfield spots =
White spots in the iris of the eye
118
What disorder are brushfield spots associated with?
Down Syndrome
119
What disorder is commonly present in DS that is also present in a lot of neurodevelopmental disorders?
Gastrointestinal issues
120
What are the 2 ways that trisomy 21 interferes with the fetal nervous system development
1. Reduction in total numbers of neurons in cortical areas
| 2. Proposed "accelerated aging"
121
What is the trend of brain weight for ppl with DS
Tends to fall below average
122
What are the 2 structure/function of neurons in DS
1. Reduced neuronal density (especially in cortical areas)
| 2. Poop synaptic connections
123
4 difficulties in learning and cognitive processing of DS
- Attention
- Info processing
- Short and long term memory processing
- Language skills
124
What do MRI scans of ppl with DS show? 3
Generalized atrophy:
- Smaller total brain size in adults
- Smaller size of the hippocampus and amygdala
125
6 Co-Morbidities of DS
- Alzheimers
- ADHD
- Aggressive behaviours
- Anxiety disorders
- Self injury
- Autism spectrum disorder
126
Growth and stature appear "normal" during the first ________ of life in ppl with DS
3 years
127
When is DS typically diagnosed?
35% at birth
46% by 2 years
Very small number after 3 years
128
In addition to Karyotyping, what other things are screened for when there is the potential for DS (4)
- Cataracts
- Blockages in gastrointestinal tracts
- Congenital heart disease
- Hearing problems
129
Are there pharmacotherapies for DS
Nothing to directly treat DS, but there are medications to treat the co-morbid symptoms (ADHD, aggression)
130
What is the treatment focus for DS?
Social, emotional, cognitive and motor abnormalities
131
What are 4 medical / social concerns for people with DS
- Independent living and employment challenges
- Difficulty developing social skills
- Improvement in symptom management has resulted in longer life (more time being dependent)
- Neurodegeneration (AD) is common
132
What is implicated in both DS and Alzheimers disease?
Amyloid precursor protein (APP)
133
Why is there such a high prevalence of Alzheimers in ppl with DS
Because the APP gene is located on Chromosome 21, and it is triplicated in DS
134
What does a brain of a person with DS look like in comparison with Alzheimers?
Even more cortical atrophy
135
What are the two directions of axonal transport
Anterograde and retrograde
136
Anterograde transport:
Transportation from the cell body to the terminal
137
Retrograde transport:
Transportation from the terminals to the soma
138
Which type of axonal transport is affected in DS
Retrograde
139
Why is retrograde transport affected in DS?
Because the excess of APP causes enlarged endosomes, and they block the axon so things cannot pass them
140
What is the animal model for DS, specifically for retrograde transport problems?
Ts65Dn mice
141
Why is abnormalities in retrograde transport a problem?
Because then the axon cannot communicate with the soma, it cannot tell it what it needs so there might be the over or under production of proteins
142
PKU is the mutation in the gene from what enzyme?
Phenylalanine Hydroxylase (PAH)
143
What does PKU stand for
Phenylketonuria
144
What genetic inheritance pattern does PKU follow?
Autisomal recessive
145
Other than genetics, what can PKU be caused by?
Abnormals levels of dietary phenylalanine
146
What is phenylalanine? What is it classified as?
An essential amino acid
Classified as a Large, Neutral Amino Acid (LNAA)
147
What are essential amino acids?
Amino acids that you can only get from your diet
148
The mutation if PAH impaired the conversion of phenylalanine to _________
Tyrosine
149
What is tyrosine essential for creating in the body?
Dopamine
150
If you don't have PAH enzyme or it is dysfunctional, it can results in excess ______ . Why is this bad?
Phenylpyruvic acid
>> Can be toxic
151
What 2 metabolic things cause most if the symptomology of PKU
Excess phenylpyruvic acid
| Lack of dopamine
152
DOPA (dopamine) is also involved in the production of what? What does this phenotypically result in in the brain?
Melanin pigments
| Results in the lighter coloured dopamine cells
153
How is PKU detected? When is this done?
A blood test
Done right after birth (heel prick)
154
Why is early detection of PKU important
Early treatment prevents associated intellectual disabilities
155
If PKU is not treated, what metabolites can be seen in the blood and urine?
Urine : phenylpyruvic acid
| Blood : Phenylalanine
156
If PKA is left untreated, what problems occur
Intellectual disability/mental retardation
157
Research suggests that increased levels of what in blood contribute to the neuropsychological deficits in PKU
Phenylalanine metabolites
158
What are the names of the 3 neuropsychological hypotheses in PKU
1. Myelin synthesis and turnover
2. Competition for transport
3. Dopamine reduction
159
Myelin Synthesis and Turnover PKU Hypothesis
High levels of phenylalanine or metabolites inhibit myelin development
>> There is a delay in development of myelin and there is myelin degradation in ppl with PKU
160
What do imaging techniques show in the brains of people with PKU
Reduction in white matter (myelin)
161
What causes the degradation of myelin in PKU
Phenylpyruvic acid
162
Is it maternal or infant diet that has the most effect on PKU? Why?
Infant, because most myelination happens post natally
163
What is the Competition for Transport Hypothesis Hypothesis (3)
Phe competes with other essential amino acids for transport across the BBB
Phe tends to have a higher affinity for transporter than other LNAA
Results in an accumulation of Phe in the bloodstream and other amino acids cannot come into the brain because the Phe is tying up all the transporters
164
What other essential acid cannot enter the brain in PKU? What NT requires it?
Tryptophan
| Serotonin
165
What is the dopamine Reduction Hypothesis of PKU
Phenylalanine is not converted to tyrosine in the absence of PAH, which results in a lack of dopamine
166
What is the effect of the lask of dopamine in PKU
It effects the prefrontal cortex, which impacts executive functions
167
Why is it difficult to make an animal model of PKU
Because there are over 600 possible mutations on the PAH gene
168
What is the phenotypes of the PKU animal model with a mutation in the PAH gene? (2)
1. Lighter coloured coat (because of the tyrosine --> melanin pigment deficiency)
3. Abnormal motor skills (inability to swim)
169
What treatment of the PKU mice result in noticable changes
Phe-restricted diet
170
How is myelin affected in PKU (2)
1. Delayed development
| 2. Demyelination
171
What dietary compound contains a LOT of phenylalanine
Aspartame ("diet" food)
172
Early treatment with Phe-restricted diet reduces the ________ manifestations of PKU
Behavioural
173
2 individual differences in ppl with PKU
1. Some do not respond to treatment
| 2. Some with high levels of phenylalanine metabolites do not suffer neurological impairment
174
Which chromosome is the PAH gene on
12
175
Classical PKU
No PAH activity, enzyme is formed but not effective
176
Mild PKU
~25% residual PAH activity
177
Severity of PKU depends on ________
Genotype
| > whether there is some residual PAH activity
178
What is the main treatment for PKU
Phe restricted diet
179
What foods are permmited in a Phe restricted diet? (2)
1. Measures amounts of fruits and vegetables
| 2. Low protein: pasta, grains, and breads
180
What foods are not allowed in Phe restricted diet (6)
```
Meat
Fish
Eggs
Dairy
Nuts
Soy
```
181
What happens when a person with PKU strays from the diet
They become fatigued and start showing signs of cognitive deficits
182
How does BH4 PKU therapy work?
BH4 boosts the activity of PAH, in individuals with residual PAH activity
183
How does LNAA supplemental therapy work for PKU
The LNAA comete with Phe to cross the BBB which allows for more amino acids to enter the brain
184
What is Glycomacropeptide
A Phe-free source of protein
185
PFC in PKU
Pattern of deficits affecting projections of dopamine neuron in the frontal lobe, resulting in cognitive problems
186
What is the probable cause of the cognitive deficits in PKU
Myelin abnormalities
187
What imaging technique best shows white matter in the brain
DTI
188
What are the 2 essential and one non-essential amino acids we need to know
Essential:
- Phenylalinene and Tryptophan
Non-Essential:
- Tyrosine
189
Fear
Negative neurological state brought on by perceived presence of threatening stimuli
190
Anxiety
Neurological state "engages" when encountering sustained cues that may predict a threat
191
GAD
Generalized anxiety disorder
192
Specific Phobia
Clinical presentation of anxiety as a result of exposure to a "feared" object or situation
193
What demographic typically has a panic disorder
Younger people
194
Panic Disorder
Sudden onset of intense fear and apprehension, impending doom
195
4 categories of anxiety disorders
Social phobia
PTSD
Acute stress associated with anxiety
Separation anxiety
196
Anxiety disorder is where a person experiences ____ anxiety when separated from _____ and ______
1. Excessive
2. Home
3. Parent
197
What is separation anxiety predictive of?
Other anxiety-related issues
198
Behavioural inhibition:
Long latency to speak, play or interact with strangers
199
Behavioural inhibition is predictive of what?
Future anxiety disorders
200
Pleasant emotions activate what hemisphere?
Left
201
Negative affect activates what hemisphere
Right
202
People with anxiety have higher levels of activation of which hemisphere?
Right
203
Family pattern of anxiety
Higher rates of anxiety in children whose parents have anxiety
204
Mice lacking ______________ show increased anxiety
5HT-1A auto-receptors
205
5HT-1A regulate the release of what?
serotonin
206
In rat pups raised by inattentive moms, what three things are seen in the pup?
1. Highly reactive HPA axis
2. Increased plasma cortisol levels
3. Reduced 5-HT levels
207
What is the relationship between levels of cortisol and the levels of serotonin?
Increased cortisol can decrease the amount of serotonin
208
This balance of cortisol and serotonin is seen especially where?
In brain areas involved in the HPA axis
209
What is the medical name and the shelf name of the most common SSRI
Fluoxetine
| Prozac
210
What psychological therapy is best for anxiety disorders?
CBT
211
When pharmocotherapy and CBT are used together, what NT is affectes
SSRIs can enhance tropic factors in the brain (BDNF)
212
Why does it take a while to see the effects of SSRIs
Because it takes time for the trophic factors to become activated
213
ASD is characterized by varying degrees of impairment in: 3
Social interaction
Communication skills
Pre-occupation with a single subject or activity
214
The term "autism" was first used to depict the tendency of ______ to isolate themselves and focus on their inner life
schizophrenics
215
3 characteristics of social impairment in ASD
1. Do not like to be picked up/cuddled
2. Rarely smile/laugh in response to stimuli
3. Prefer "interacting" with objects
216
2 characteristics of communication impairment of ASD
1. High incidence of being mute
| 2. Robotic behaviour- interacting more with objects
217
2 repetitive and stereotypes behaviour patterns of ASD
1. Flapping hands, rocking/twirling repeatedly
| 2. Restricted interest - less "creative play" with objects
218
Autistic savant
Person with autism having abnormally high skill in one area
219
2 abnormal sensory perceptions in people with ASD
1. Either hyper or hypo-responsive to stimuli
| 2. Synaesthesia
220
Typical Autism
Impairment across all core symptoms
221
4 core symptoms of typical autism
1. deficits in social functioning
2. Lack of emotional reciprocity
3. Impaired verbal and non-verbal communication
4. Repertoire of repetitive, restrictive and stereotyped behaviours
222
Atypical Autism
Impairment in all three core domains, but full diagnostic criteria for pervasive developmental disorder (PPD) not met
223
3 core domains in atypical autism
1. No significant cognitive impairment
2. No significant abnormality in language development
3. "intact" social skills
224
Is atypical autism more mild then typical autism?
Not necessarily
225
"Low functioning" autism refers to being _____ responsive
Hypo
226
"High functioning" autism refers to being _____ responsive
hyper
227
High functioning autistics usually have _____ average intelligence and low function usually have _____ average intelligence
Above
| Below
228
Often children with autism start developing normally and then what?
There is noticeable impairment between 2 and 3
229
What 3 impairments appear at 2-3 in autism
1. Deterioration in language skills
2. Loss or impairment in social behaviour
3. Onset of stereotypes or repetitive behaviours
230
Most of the cases of autism are ___ cause
idiopathic
231
Environmental toxin OR genetic abnormality are associated with ____% of autism cases
15%
232
There is a high incidence of what brain abnormality with autism
Microcephaly
233
Complex autism:
evidence of some abnormality of early brain development
234
Essential autism:
met the diagnostic DSM5 criteria for autism
| > No obvious brain abnormalities
235
There is a suggested chromosomal abnormality is ___% cases of autism
90%
236
What genes are involved in autism
Unknown but it is thought to be polygenic
237
5 Environmental factors associated with autism
1. Prenatal infections (viral)
2. Peri-natal brain damage
3. Heavy metal exposure
4. Pesticide/herbicide
5. BPA
238
What heavy metal might be associated with autism
Mercury
239
What is the controversial chemical in vaccines that "might" be associated with autism
Thimerosal
240
What is the active ingredient in weed killer that has been "associated" with autism
glyphosate
241
High levels of what NT at birth has been associated with autism?
BDNF
242
Why is it thought that high levels of BDNF in the blood at birth could be associated with autism
BDNF that is produced in the brain might be leaking out so there is not enough in the brain to facilitate proper growth and protection
243
2 teratogins that have been linked to autism
1. Alcohol
| 2. Valproic acid (mood stabilizer)
244
Greater frequency in ________ disease in families with high prevalence of autism
autoimmune
245
What antigen might be implicated in autism?
Human leukocyte (HLA)
246
Abnormalities in the function of 3 cytokines/chemokines have been suggested to be linked with autism
1. Interleukins
2. TNF
3. Interferon gamma
247
Cerebral volume in autism (3)
1. Smaller cell size
2. Increased cell density
3. Premature over production of neurons
248
Amygdala in autism
Difficulty with emotional response
249
Hippocampus in autism (3)
- enlarged
- smaller neurons
- cells packed more densely
250
Serotioin in autism
Levels are elevated
251
Why are there higher incidence of seizures and anxiety disorders in people with autism
Because there is an imbalance in GABA and Glutamate
252
What are mirror neurons essential for? (3)
1 Ability to understand and imitate others' actions
2 Allows for empathy
3. Facial and emotion recognition
253
Where are mirror neurons typically locate? (2)
Inferior motor cortex
| Superior parietal lobe
254
There are no drugs that directly treat autism, but there are drugs that treat the associated symptoms, what are they (4)
Haloperidol
Risperidone
Methylphenidate
SSRIs
255
What type of drug is haloperidol and what is it used for in autism
Typical antipsychotic
| Used to treat aggression and hyperactivity
256
What type of drug is risperidone and what it is used to treat in autism?
Reduction in irritability, aggression and injury
257
Risperidone affects what NT
Serotonin
258
What is methylphenidate used for in autism
Treat ADHD symptoms
259
What are SSRIs used for in autism (2)
- Decrease repetitive behaviours
| - Improve language and social skills
260
What alternative medicine is used to treat autism
Managing diet to target gastrointestinal problems
261
What is the most common MONOgenic inheritable form of mental retardation
Fragile X Syndrome
262
FXS is inherited from an error in what gene
FMR1
263
What protein is affected in FXS
FMRP
264
Is FXS more common in males or females
Males
265
Broad spectrum of disabilities for FXS (3)
- Learning disabilities
- Mild to moderate intellectual disabilities
- Cognitive impairment
266
~____% of people with FXS show autistic characteristics?
30%
267
4 physical features of FXS
- Pong/prominent ears
- Long face
- Flat feet
- Cardiac murmur
268
What is Fragile X-associated primary ovarian insufficiency
Ovarian cysts and premature menopause in women
269
3 Behavioural features of FXS
- Short attention span
- Impulsivity
- Hyperactivity
270
What is the abnormal amino acid repeats on the FMR1 gene
CGG
271
Normal CGG repeats on FMR1
5-40
272
Pre-mutation CGG repeats on FMR1
55-200
273
Full mutation CGG repeats on FMR1
more than 200 repeats
274
What is the normal function of CGG repeats on the FMR1 gene
Recruiting methylation (silencing) groups
275
The more CGG results in more _____ with causes ______ FMRP to be made
Methylation/Silencing
| less
276
How much FMRP is made in pre-mutation FXS
Less than normal protein made
277
How much FMRP is made is full mutation FXS
No protein made
278
FXS is more sever in males or females? Why?
Males
It is an X linked disorder, and males have only one X chromosome, so there is nothing to compensate for the mutated chromosome
279
3 possible inheritance patterns with FXS carrier parent
Normal
Pre-mutation
Full mutation
280
CGG repeats are located where on the FMR1 gene?
Front end, in the promoter regions
281
What does it mean for transcription that the CGG repeats are at the promotor region of the gene in FXS?
Transcription factors are inhibited from binding to the DNA so transcription cannot happen
282
What is FXTAS?
Fragile X associated tremor/ataxia syndrome
| >>Late onset neurodegenerative disorder
283
What form of FXS can FXTAS occur in?
Pre-mutation and full mutation
284
What cellular function is FMRP integral for?
RNA transport and regulation
285
What are the intranuclear inclusions in FXTAS made of?
Pre mutation --> RNA and abnormal FMRP build up
| Full mutation --> just RNA build up
286
Why do the intranuclear inclusions happen in FXTAS?
FMRP is supposed to regulate the production of RNA and RNA transport, but when there is not enough if it, RNA gets over produced and it is not able to exit the nucleus, so it builds up
287
What is the late onset neurodegenerative disease that is associated with FXS
FXTAS
288
Many ____ mutation patients develop FXTAS
pre-mutation
289
FMR1 pre-mutation carriers show intra-nuclear brain inclusions that can result in (3)
1. Parkinsons
2. Motor abnormalities
3. Significant cognitive deficits
290
FMRP deficiency results in dysregulation in:
global protein expression in the brain
291
What are mGluR5? What do they do (2)
Metabotropic Glutamate Receptor
1. Function in synaptic plasticity and learning
2. Longer term depression
292
What disorder is long term depression commonly seen in
FXs
293
FXS often causes more or less mGluR5 in the brain? What does this result in?
More
| Results in too many synaptic sites
294
There is an __________ of synpatic spines in FXS but they are ________
Over-abundance
| Immature
295
Long term potentiation (LTP)
Long term strengthening of synaptic interaction between neurons
296
Long term depression (LTD)
Weakened synaptic strength between neurons
297
In FXS, long term depression promotes what?
Weak synaptic connections
298
Relationship between mGluR5 and long term depression
More mGluR5 results in enhanced LTD because even though there are lots of connections, they are weaker connections
299
Why is it that as people with FXS age they have degreased cognitive abilities?
More neurodegeneration from the intranuclear inclusions
300
What 2 brain areas are enlargened in people with FXS
Caudate and thalamus
301
What could the enlarged caudate explain?
the ADHD symptoms
302
People with FXS are often misdiagnosed as having
Autism
303
What is the treatment for FXS
No cure so the treatment is for symptoms
304
What atypical antipsychotic drug can be used for FXS
Abilify
305
The drug minocycline is though to reduce what in FXS
Reduce matrix metalloporteinase 9 (MMP-9)
306
MMP levels are high in the absence of ____
FMRP
307
High levels of MMP-9 is correlated with what?
Brain damage q
308
FMRP regulates the ____ protein
APP
309
What is the function of APP?
It regulates the number of spines on dendrites
310
More APP in people with FXS is related to what? (3)
- Alzheimer's disease
- Increased intellectual disability
- More immature spines
311
Lack of FMRP leads to ______ BRD4
more
312
What layer of primordial tissue develops into the nervous system?
Extoderm
313
What 3 things does the ectoderm develop into
- CNS
- PNS
- Skin
314
what is the process of gastrulation?
Blastula will invaginate and then close up to form the neural tube
315
What is the notochord?
Area under the neural tube that is important in sending the signals for the development of the nervous system
316
3 stages of neural tube
Neural plate --> neural crest --> neural tube
317
What week does gastrulation occur?
~3rd week of pregnancy
318
When does neurolation occur?
within the first 4 weeks of pregnancy
319
What is the implication of gastrolation and neurolation happening so soon in the pregnancy
The women might not know she is pregnant yet so she is not living the best lifestyle
320
Anencephaly
Absence of major portion of the brain/skill
321
What is the prognosis of anencephaly?
Early mortality
| Baby does not make it to term or dies soon after birth
322
Spina bifida
Incomplete closure of the neural tube
323
What is the most common form of spina bifida
myelomeningocele
324
What are the 2 broad categories of spina bifida?
Occulta
| Cystica
325
What is spina bifida occulta
Incomplete closure of posterior spinal column but it does not result in any symptoms
326
What is spina bifida cystica
Cystic formation overlying the defect on the spinal column
327
What are the 3 types of spina bifida cystica
Meningocele
Lipomeningocele
Myelomeningeocele
328
Meningocele
Herniation of meninges but no neurons
329
Lipomeningocele
Herniation of meninges and fat, but no neurons
330
Myelomeningeocele
Herniation of meninges, fat AND neuronal matter
331
What is the most serious form of spina bifida
myelomeningeocele
332
What causes cognitive deficits in spina bifida
Interruption in the flow and circulation of CSF
333
Genetic link of spina bifida
Over 200 genes have been implicated but causal factors still unknown
334
Environmental risk factors of spina bifida (3)
1. Increased intrauterine temperature (fever)
2. Medications
3. Diet
335
What diet deficiency is related to spina bifida
Folate (Vitamin B9)
336
What medication is associated with spinabifida
Antiepileptics such as Valproic Acid
337
What developmental process is folic acid necessary for?
Myelination --> turning off genes at the proper time
338
Valproic acid increased what NT? What effect can affect can this have on the nervous system?
Increases GABA
| Might inhibit movement which would impact the activity dependent mechanisms in the NS
339
The defect is usually seen at what two levels in the spinal cord with spina bifida. What can this cause?
Thoracic and lumo-sacral
Can cause chronic pain
340
There are usually _____ and ____ deficits below the defect in spina bifida
motor and sensory
341
4 Other common physical features of spina bifida
- Bowel and bladder issues
- Orthopedic complications
- Sleep disordered breathing
- Latex allergy
342
Hydrocephalus is commin in spina bifida. What can this affect?
Visual-perceotual and motor functioning
343
What imaging tests are done to screen for spina bifida
Ultrasound, and then an MRI to confirm
344
What is often seen on an MRI of people with spina bifida
Agenesis of the corpus callosum = premature degeneration
345
What is done to treat the hydrocephaly in spina bifida
A shunt in installed to drain the excess fluid
346
Seizure
Abnormal brain activity
347
What percentage of people who have experienced a seizure develop epilepsy?
1/3
348
Epilepsy
Recurrent disturbances in electrical activity in the brain resulting in seizures
349
Why are seizures more common in children under 5
Because the immature brain is more excitable
350
What is the hypothetical link between microglia and seizures? (3)
Results in:
- increased neuronal excitability
- decreased trophic factors
- altered synaptic pruning
351
Mutations in _______ gives you a higher vulnerability for seizures
voltage gated sodium channels
352
What is the gene that gets mutated that results in abnormal voltage gated sodium channels
Sodium channel, Voltage-gated type 1-A (SCN1A)
353
What type of mutation caused the SCN1A mutation in epilepsy
Missense mutation
354
There are reduced sodium channels in what type of neuron? This leads to what?
GABAergic interneuron
Results in decreased inhibition
355
Environmental factors that are known to induce seizures (3)
- Fever
- Increased stress/excitation
- Prone to anxiety
356
Even though there aren't structural abnormalities with epilepsy, there are often what abnormalities
Functional
357
What is used to detect functional abnormalities in epilepsy
DTI
358
Classification of seizures (3)
1. Symptomatic (known environmental trigger)
2. Cryptogenic (cause undetermined cause, but related to other cognitive condition)
3. Idiopathic
359
Progressive unilateral encephalopathy
A totally healthy person suddenly has a seizure of no known cause
360
Brain function abnormalities in epilepsy
Often deficiencies in executive function and motor abnormalities
361
What are the 2 anti-convulsants often used to treat epilepsy and how do they work?
1. Clonazepam (benzodiazepine) - binds to GABA neuron and induces inhibition
2. Valproic Acid (blocks sodium channels)
362
Seizure activity can increase what NT
BDNF
363
More BDNF does what to synapses?
Causes more synapses to be formed and thus allows for more excitability
364
Why can too much BDNF be bad?
It increase excitatory synaptic connections which can cause hyper excitation in the brain and result in a seizure
365
Retts syndrome is part of what spectrum of disordeers?
Autism spectrum
366
What is the most common cause of mental retardation in females
Retts syndrome
367
What is the typical course of development in someone with Retts
they will develop normally in infancy and normal childhood and then there will be a significant developmental degeneration
368
Classical or Typical Retts
Symptoms emerge between 6-18 months of age
369
Atypical Retts
Symptoms appear early (soon after birth) or late (after 18 month-4 years old)
370
Retts is most common in females, can makes have this disorder?
Yes but they often die soon after birth
371
What is the symptomology pattern in people with atypical Retts
Heterogeneous (individual variation) and the symptoms are less severe
372
Pre-stage 1 Retts
Normal early development
373
Stage 1 Retts: Early onset stagnation
6-18 months
| Only see stereotyped hand movements and loss of interest
374
Stage 2 Retts: Rapid destructive
18months
| Language and motor deterioration
375
Stage 3 Retts: Plateau
1-10 years
| Breaking, sleep and motor abnormalities
376
Stage 4 Retts: Late motor deterioration
Motor and intellectual disabilities
377
Retts is linked to mutations in what gene?
MECP2
378
What chromosome is MECP2 on?
X chromosome
379
What does the MECP2 gene do?
It is a member of the methyl-binding protein family that silences genes to regulate transcription
380
Where is the MECP2 gene expressed
In the brain and other tissues
381
There is increased expression of MECP2 as we age?
In the cortex
382
What is MECP2 thought to be integral for because it increases in the cortex with age?
Regulating and maintaining the state of the nervous system
383
In Rett syndrome, a mutation to the MECP2 gene results in what for the protein?
Reduced or eliminated function of the MECP2 protein function
384
What does a lack of MECP2 protein function impair normal neurodevelopment?
Because many genes stay turned ON at inappropriate times during development
385
Percentage of Retts associated with a:
1. missense mutation
2. Nonsense mutation
3. C-terminal deletion
4. Large deletion
1. 39%
2. 35%
3. 8.7%
4. 6.4%
386
Frame shift mutation
When a nucleotide is deleted or inserted that results in a DIFFERENt amino acid at the point o f mutation that results in a STOP codon
387
Nonsense mutation
Single nucleotide polymorphism (switch) which leads to a STOP codon
>>Still have same # amino acids
388
Mis-sense mutation
A single nucleotide polymorphism (switch) that results in a different amino acid being produced, but does not affect sequence or length f protein
389
What is the issue with producing a premature stop codon?
The protein does not get fully formed and is shorter
390
What is the problem with having a different amino acid?
Can affect protein folding
391
All mutations can affect __________ with can change how the protein will eventually function
Post translational modification
392
There are less severe symptoms of Retts when:
the mutation allows the protein to be longer so the protein does not lose all function
393
Missense mutation T158M in Retts
Threonine 158 converted to methionine
394
A T158M knock-in animal model provided evidence for what?
A causal roll of MECP2 mutation in the development of Retts like symptoms
395
What symptoms did the T158M animal model for Retts show? (3)
- Developmental regression
- Motor dysfunction
- Learning and memory deficits
396
MECP2 regulates what NT, what affect does this have on development
BDNF
| Imacts neuroplasticity
397
MECP2 also regulates the production of what kinase?
Cyclin dependent kinase 5 (cdk5)
398
MECP2 _______ cdk5 expression when normally functioning
repressed
399
What is CDK5 vital for during neurdevelopment
Layering pattern of the cortex
400
What white matter tract is 30% smaller in people with Retts
Corpus callosum
401
There is an overall _____ in white and grey matter in Retts
reduction
402
There are small neurons in what 5 brain regions in Retts
```
Cerebral cortex
thalamus
basal ganglia
amygdala
hippocampus
```
403
There is an overall ____ in the number of synapses in Retts
reduction
404
There are low levels of what 3 NT monoamine in Retts syndrome
Dopamine
Serotonin
Norepinephrine
405
What is theMonoamine Hypothesis of RTT
Early lesions in the midbrain and brainstem areas lead to inadequate synaptogenesis
406
The lack of regulation by MECP2 leads to higher levels of glutamate in Retts which results in what?
Hyperexcitability of vast numbers of neurons in the brain
407
Can Retts be cured?
No
408
What is the structure of the mitochondria
Tube shapes with double membranes, there is an inner-membrane space and mitochondrial matrix
409
mtDNA stands for
mitochondrial DNA
410
What is the mitochondria essential for?
Producing energy for the energy hungry neurons
411
Cristae
Folds of the inner membrane of the mitcho
412
Matrix
Inside inner membrane of mitcho
413
Intermembrane space
space beteen mambranes of mitcho
414
What things are located in the inner membrane
Mitochondria DNA and electron transport chain
415
Which parent are mitochondria inherited from?
Mother
416
Why is there a high rate of mutation in mitcho DNA
Because it does not have effective repair mechanisms
417
What are the symptoms of mitochondrial DNA disorders?
High variability because there are many different types of mutations
418
How can mutations in the nuclear DNA affect mitochondrial function?
Proteins made by the nuclear DNA are used in the mitochondria
419
Mitochondrial myophathy is a common mitochondrial disorder, what is it characterized by?
significant neuromuscular abnormalities
420
What is Leigh Disease caused by and what does it affect
30 mutations in mtDNA
| >>>Affects Cytochrome C Oxidase (COX)
421
What is Cytochrome C Oxidase
Complex 4 of the electron transport chain
422
Why is the mitochondria often affected by oxidative stres?
It deals with a lot of oxygen to ROS can build up and kill the cells
423
What is retrograde communication
Pathway of communication from the mitochondria to the nucleus
424
How can a dysfunctioning mitochondria alter the expression of proteins in a cell
Mitochondria will not produce enough energy so it will send signals to the nucleus to stop producing so many proteins to conserve energy
425
What ion does the mitochondria heavily regulate? If the mitcho is not regulating it properly, what is affected?
Calcium
It will affect the neurons ability to communicate
426
When mitochondrias are not working properly what cells are most affected?
Cells that require a lot of energy like neurons and muscle cells
427
Leigh disease is a subtype of Subacute Necrotizing Encephalomyelopathy. Ways does that mean
```
Subacute = rapic onset of symptoms
Necrotizing = irreversable neuron death
Encephalomyelo = nervous system: brain and spinal cord
```
428
When complex 1 is not functioning in mitochondria it cannot produce energy. What does this result in?
A starvation of the neurons where they cannot function
429
Mitochondrial dysfunction contributes to what type of cell death the most. What disease is it correlated with
Dopaminergic cells
Parkinsons
430
MPTP is taken up by what types of cells?
Dopamine cells
431
What does MPTP do when it is taken u pby dopamine cells?
Inhibits complex 1 of the electron transport chain, which starves the cells and kills them
432
The loss of dopamine neurons caused by MPTP kill what brain structure and results in what type of symptoms
Kills neurons in the substantia nigra and causes Parkinson like symptoms
433
Retrograde communication of the mitochondria with the nucleus can cause what types of epigenetic changes
Influences DNA methylation patterns
434
Any abnormalities in complex 1 and complex 4 in the mitochondria can result in the production of what whoch causes neurodegeneration of neurons
Reactive oxygen species
435
What are the neuroactive drugs in cannabis
THC and cannabidiol (CBD)
436
THC binds to what receptors in the brain
cannabinoid receptors
437
When THC binds to the cannabinoid receptors in the brain, what does it do?
Mimics the effects of endogeneous cannabinoids (endocannabinoids)
438
What are the two main endocannabinoids in the brain?
Anandamine (AEA)
| 2-AG
439
Endocannabinoids are lipophilic, what does that mean for transport?
Can cross the BBB and placental barrier
440
What are the 2 major G-protein coupled receptors in the brain?
CB1-R
| CB2-R
441
Which of the 2 cannabinoid receptors are found most in the brain
CB1
442
Where is anandemide produced?
In the post-synatic cell
443
Where is the CB1 receptor located and stimulated?
On the pre-synaptic cells
444
Endocanabinoids use neuomodulatory signalling, what does that mean
Anandemide is produced in the post-synaptic cell, and then is sent to the presynaptic cell to stimulate the CB1 receptors and regulate pre-synaptic neurotransmission
445
What NT will be affected by endocannabinoids?
MANY
446
What is the effect of endocannabinoids affecting the release of many NT
It will effect global NT homeostasis in the brain
447
What receptor does THC stimulate?
CB1
448
How is neurotransmission affected when THC stimulates that CB1 receptor
CB1 activation results in inhibition of calcium mediated vesicular neurotransmitter release
Has global impact because the CB1 receptor regulates the release of many NT
449
CB1 activation can inhibit calcium influx or efflux
influx
450
What stages can cannibis affect neurodevelopment?
Any stage,
451
What do the effects of cannabis exposure on neurodevelopment depend on?
- Timing/age of exposure
- duration of exposure
- Dosage of exposure
- Route of administration
452
The _______ brain is vulnerable to the compounds present in cannibis
immature
453
How long can the metabolites of cannabis be detected after exposure
weeks after
454
Both neuro____ and neuro______ effects of TCH and CBD have been observed in vitro
neuroprotective and neurotoxic
455
The neurotoxic and neuroprotective effects of cannibis have been dseen in what cell types (2)
Cortical and hippocampal
456
There is more significant neurotoxic effects of cannabis in the hippocampus and cortex for what age groups
Adolescents
457
The espression pattern of CB1 receptors in the developing brain suggest a role in whay two processes?
1. Axonal migration
| 2. Synaptogenesis
458
Endocannabinoids may also play a role in regulating the survival of what cells during neurodevelopment
Neural progenitor cells
459
Over stimulation of the CB1 receptor can have what effect on a developong btain?
Can throw off the normal developmental trajectory
460
Prenatal exposure to cannabis has been potentially linked to what 3 types of disorders?
1. Spina bifida
2. Cognitive deficits
3. Motor deficits
461
Why is cannibis more able to get into the fetal brain?
The immaturity of the BBB may facilitate transportation
462
Adolescent cannabis use has been observed to result in what structural abnormality
Lower proportion of gray matter relative to whole brain volume
463
What critical process is happening in adolescent brains that may be disrupted with the use of cannabis (3)
The maturation of the PFC
Myelination
Synaptic pruning
464
Cannabis use can mimic the symptoms of what psychiatric disorder
schizophrenia
465
Increased expression of CB1 receptors and endocannabinoids has been observed in the braons of ______ patients
schizophrenia
466
Marijuana use prior to the age of ____ is associated with greater risk of schizophrenia by 18
15
467
Pluripotent cells
embryonic cells that can develop into any type of cell
468
Multipotent cell
Embryonic cells that can differentiate into a few types of cells
469
Neural stem cells
Embryonic cells that can differentiate into either neuron or glial cells
470
Induced pluripotent stem cells
Taking an adult cell an using a chemical cocktail of transcription factors to revert adult stem cells into pluripotent cells
471
What can induced pluripotent stem cells be used for?
Developing cell-based therapies and can also be used as a model and study disease mechanisms
472
What disorder is induced pluripotent stem cells especially useful for studying?
Down syndrome because there are no good animal models
Can can be used to study the different types fo DS
473
If a mother exercises while pregnant there has been seen to be an increase in what NT what can result in a more ",=mature" brain at 18 months
BDNF
