module 2 Flashcards
what is the difference between emotion and mood
emotion: intense feeling that is short-term and typically directed at a source
mood: state of mind that tends to be less intense than an emotion and does not necessarily need a contextual stimulus
what are the three components of emotion
behavior
physiology
feeling
what are the 6 basic emotions
anger
sadness
happiness
fear
disgust
surprise
what part of the brain was needed to produce sham rage (not directed at a target) in cats
caudal hypothalamus
where are basic circuits for emotion concluded to be found
in the diencephalon
where is the site of associative learning of fear
amygdala
what was significant about patient S.M
bilateral destruction of amygdala
- showed all emotions except fear
what areas are seen as important for emotion
orbital and medial prefrontal cortex
amygdala
thalamus
hypothalamus
stratum
what areas of the brain are no longer considered important neural centers for processing emotion
hippocampus
mammillary bodies of the hypothalamus
what are the three catecholamines
dopamine
epinephrine
norephinephrine
what are the four monoamines
dopamine
epinephrine
norepinephrine
serotonin
what AA are catecholamines produced from
tyrosine
what AA is serotonin produced from
tryptophan
where are NE neurons located
locus coeruleus
where do NE project
all over the brain
where are epi neurons located
medullary epinephrine neurons
where do epi neurons project
not as widely spread throughout brain
what gland synthesizes NE and epi
adrenal gland
what is the pathway from tyrosine to NE/epi
tyrosine - (tyrosine hydroxylase) -> DOPA –> dopamine –> NE/epi
how does NE, epi, dopamine, serotonin get into vesicles
VMAT (vesicular monoamine transporter)
what does the NET do
norepinephrine transporter
- removed NE from synaptic cleft and back into presynaptic cell (GPCRs)
what receptors are on the postsynaptic neuron that bind NE and epi
postsynaptic adrenergic receptors
alpha 1, alpha 2, beta
what enzymes are present on mitochondria that metabolize NE, epi, and dopamine
COMT - catecholamine methyl transferase
MAO - monoamine oxidase
what two drugs block dopamine reuptake
cocaine
amphetamines
where are serotonin neuron cell bodies
raphe nuclei
where do serotonin neurons project to
extensively branched
what is the pathway from tryptophan to serotonin
tryptophan - (tryptophan-5-hydroxylase) -> 5-hydroxytryptophan -> serotonin (5HT)
what transporter brings 5HT back into the presynaptic terminal
5HTT
are serotonin receptors on the post synaptic neuron metabotropic or ionotropic
both
what is the serotonin presynaptic receptor called
presynaptic serotoninergic receptor
what enzymes are on the mitochondria that break down serotonin
MAO - monoamine oxidase
what is the relationship between serotonin and the enteric NS
serotonin inhibits peristalsis
what is responsible for the variation in serotonin transcriptional efficiency
polymorphic gene promotor
- long and short polymorphism both produce the same protein but the quantity of protein synthesized is different
what is difference between the long and short serotonin allele
long: higher levels of transporter protein (less serotonin in synaptic cleft)
short: lower levels of transporter protein
is the long or short serotonin allele more likely to result in depression
long because there is more serotonin being transported out of the synaptic cleft
where are dopamine cell bodies located in the brain
substantia nigra and ventral tegmental area
where do dopamine neurons project to
all over the brain
what is the pathway to make dopamine from tyrosine
tyrosine - (tyrosine hydroxylase) -> DOPA -> dopamine
what transporter takes dopamine back into the presynaptic neurons
DAT - dopamine transporter
what are the dopamine receptors on the postsynaptic terminal
D1 and D5: excitatory
D2, D3, D4: inhibitory
all GPCRs
what is the most important way to remove monoamines from the synaptic cleft
reuptake
DAT
NET
SERT
where are enzymes to break down catecholamine located
both neurons and glial cells
what is MAO and where is it found
2 forms of monoamine oxidase are located on the presynaptic mitochondria (A and B)
what is COMT and where is it found
catechol-O-methyl transferase
in pre and post synaptic cells
- only for catecholamines (not serotonin)
what was the milner and olds experiment
implanted an electrode in the pleasure center (DA secreting neurons) and the rat pressed a lever to receive stimulation
- rat would keel pressing lever to the point of extreme exhaustion
what is the primary reward circuit
VTA-NAc
dopaminergic projections from the VTA to the NAc
- NAc releases DA in response to reward related stimuli
what is the lateral habenula
important part of the reward circuit that provides negative value signals to dopaminergic and serotonergic systems
how are LHb (lateral habenula) neurons excited
when reward is less than expected
activity is reduced when a go response is elicited
excited by unexpected non-rewarding or unpleasant events
inhibited by unexpected rewarding events
what is reward prediction error
positive RPE - reward is greater than predicted and the action associated with the reward is facilitated
negative RPE - actual reward is smaller so the action is suppressed
what does the hypothalamus control
homeostasis
- outputs to the autonomic nervous system and pituitary gland (HPA axis)
what is essential for circadian rhythms
suprachiasmatic nucleus (SCN)
how do releasing factors travel from the hypothalamus to the anterior pituitary
dedicated portal system
what do releasing factors do
stimulate release of stimulating hormones
what do stimulating hormones do
enter blood stream and travel to various areas leading to secretion of hormones
what is the HPA axis
hypothalamus: CRH
pituitary: ACTH
adrenal gland: cortisol
what can increased cortisol lead to
loss of synapses and decreased synaptic complexity in prefrontal cortex
reduced BDNF
altered glucocorticoid receptors
what do antidepressants try to reverse
the symptoms associated with increased cortisol levels
what is bipolar I
at least one episode of mania and episodes of major depression
what is bipolar II
at least one episode of hypomania and one depressive episode
what is cyclothymia
cycling mood
- does not meet the criteria of major depression and hypomania
what is the mean age of onset for bipolar disorder
~20
what are two drugs that can induce manic episodes
cocaine
amphetamine
what drug can lead to early onset of bipolar disorder
THC
how many regions of genes are identified as contributing to bipolar disorder
18 regions (not genes)
what are three environmental factors that can contribute to bipolar disorder
early trauma
substance use
stressful events
what is the most effective drug for bipolar depression
lithium
what are the 4 categories of drugs used to treat bipolar disorder
mood stabilizers: lithium and valproate (anticonvulsant)
antipsychotics: thorazine, quetiapine, risperidone (common schizophrenia drugs)
antidepressants
anxiolytics (antianxiety): GABA agonists
what are symptoms of major depressive disorder
sad mood, anhedonia, recurrent suicidal ideation
what is disruptive mood dysregulation disorder (DMDD)
seen in children and adolescents with frequent anger outbursts and irritability out of proportion to the situation
what is persistent depressive disorder (PDD) or dysthymia
depressed mood that is not severe enough to meet the criteria for a major depression disorder
what is premenstrual dysphoric disorder (PMDD)
characterized by irritability, anxiety, depression, and emotional lability occurring a week before the onset of menses followed by resolution of symptoms after onset
what is postpartum depression
MDD after giving birth
what is seasonal affective disorder (SAD)
MDD with a seasonal pattern
what is an example of learned helplessness in mice
unpredictable, uncontrollable stress like a foot shock
what is chronic social defeat stress (CSDS) in mice
mild-mannered mice paired with aggressive mice for several weeks and eventually the docile animals exhibit anxious and withdrawn behavior
what is an example of helpless entrapment in mice
forced swim test in water without way to escape
what is the concordance of a disorder
the degree to which it is inherited
what does polygenic mean
no single gene can be linked to a cause of all the symptoms
what are two genes that are hypothesized to be associated with depression
calcium channels
glutamate receptors
what are two genes that are known to be associated with depression
polymorphism in the promotor and in second intron (VNTR) of the 5HTT gene
epigenetic regulation of BDNF gene
what does BDNF signaling modulate
LTP (long term potentiation)
- BDNF enhances LTP by both modulating presynaptic release of NT and postsynaptic growth of spines
what is mTOR
mechanistic target of rapamycin
what does mTOR do
coordinates cell growth and metabolism with environmental inputs (nutrients and growth factors)
serine/threonine protein kinase
how is BDNF stored and released
stored in vesicles and released in an activity dependent manner
what receptors bind BDNF
both presynaptic and postsynaptic TrkB receptors
how does BDNF affect proteins
global effect on translation of proteins
what is the relationship between stress and dendrites
stress causes atrophy of dendrites and decreased number and size of dendritic spines
what are epigenetics
regulation of gene expression
- no changes in DNA sequence
what are the three steps of epigenetics
- methylation
- acetylation
- RNA based modulation
what is the role of the methylation step in epigenetics
methylation of cytosine nucleotides of DNA silences RNA transcription
methylation inhibits transcription
what is the role of the acetylation step in epigenetics
acetylation of histone proteins interferes with DNA-histone interactions and exposes DNA segments so they are accessible to transcription machinery
acetylation increases transcription
what is the role of RNA based modulation in epigenetics
RNAs can increase or decrease transcription of a gene by interacting with DNA and histones
what are six things that decrease or are reduced in depression (structural changes)
- reduced medial prefrontal cortex
- reduced hippocampus
- reduced size of pyramidal neurons
- loss of GABAergic neurons
- reduced glia in hippocampus
- decreased number of spines in hippocampus
what increases in depression (structural changes)
increased size of amygdala and more complex dendritic tree
what happens to inflammation during depression
increased levels of proinflammatory factors such as cytokines (interleukins and tumor necrosis factor)
what does ketamine block
NDMA receptors on interneurons (more than other neurons) which inhibits GABA release
(less inhibition because less GABA release)
where are neuroblasts found (where neurogenesis is seen in adults)
in the subgranular zone (SGZ) of dentate gyrus and subventricular zone of the lateral ventricles
what happens to BDNF and its receptors in depression
they are reduced
what does reducing BDNF lead to
anxiety
what do mood stabilizing drugs promote
neurogenesis
what drug restores changes in dendritic morphology resulting from depression
lithium
what are the three subtypes of antidepressants
tricyclic
MAOI
SSRI/SNRI
what is esketamine
ketamine nasal spray used for treatment resistant depression
- has to be administered in a clinical setting
what is bupropion
norepinephrine and dopamine reuptake inhibitor
what drug has been used for postpartum depression
derivative of progesterone
positively modulating GABAA receptors
what is schizophrenia
disorder of cognitive abnormality and abnormality of sequential thought
(causes people to interpret reality abnormally)
what is psychosis
refers to a collection of symptoms that affect the mind - some loss of contact with reality
what are hallucinations
perceptions with no external stimuli
-auditory or visual
what are illusions
severely distorted perceptions
what are delusions
unrealistic beliefs that can’t compare with reality
what are the three classes of symptoms for psychosis
positive (addition)
negative (removal)
cognitive
when does schizophrenia usually develop
late adolescence and early adulthood
what innervation increases dramatically during late adolescence and early adulthood
dopamine innervation of prefrontal cortex
what are three ways circuits are refined during early adulthood
pruning of asymmetric (excitatory) synapses
proliferation of inhibitory circuits
continued elaboration of pyramidal dendrites as targets of inhibitory input
what part of maturation is compromised with schizophrenia
final burst of maturation of the cortex
where does the mesocortical pathway project to
prefrontal cortex
where does the mesolimbic pathway project to
hippocampus
cingulate
amygdala
olfactory bulb
what is the dopamine hypothesis
increased dopamine levels result in schizophrenia
what is haloperidol
D2 antagonist that reduced psychotic symptoms
(lead to dopamine being considered the underlying cause)
what was the mechanism of haloperidol
increased synthesis and release of dopamine
no change in D2 receptors
no change in dopamine transporters
what are some structural white matter changes in schizophrenia
overall reduction in white matter volume
reduced myelination (oligodendrocytes decrease)
fornix and cingulum reduced
what structure enlarges in schizophrenia
ventricles
where is there enhanced activity (1) and decreased activity (2) in the brain with schizophrenia
enhanced activity in the DLPFC
decreased activity in the amygdala and hippocampus
what are some of the GABAergic deficits seen in schizophrenia
reduction in GABAA receptors
reduced number of interneurons
50%reduction in GABAergic synapses
what are some glutamatergic deficits in schizophrenia
smaller pyramidal cells
reduced NMDA receptors
increased levels of glutamate in untreated patients and decrease after treatment
what are some dopaminergic deficits in schizophrenia
decreased dopaminergic innervation of PFC
increased dopamine receptors
what are the two kinds of GABAergic cells
chandelier: inhibit initial segment of axon
basket: inhibit cell body
what are gamma oscillation a result of
rhythmic depolarizing glutamatergic activity and hyperpolarizing GABAergic activity of pyramidal cells
what is the amplitude of gamma waves increased by
working memory load
what are mutations in the major histocompatibility complex (MHC) genes associated with
schizophrenia
how are synapses pruned in schizophrenia
in an activity-dependent fashion
- C4 complement protein tag synapses to be removed
- microglia surrounding the synapse recognize the tag and remove the synapse
(more synapses are removed in schizophrenia)
what is the mechanism of overactive pruning in schizophrenia
microglial dysfunction and mutation of C4 gene
what happens to the spine density in the DLPFC in schizophrenia
it decreases
what happens to the connectivity of the brain in schizophrenia
atypical connectivity rather than overall reduction in connections
what is the glutamate hypothesis
schizophrenia is due to hypofunction of NMDA receptors
what do PCP and ketamine (NMDAR antagonists) mimic
psychosis
normally, how is dopamine release inhibited
glutamate inhibits dopamine release via activation of GABAergic neurons
how can over pruning of spines during development cause enhanced dopamine release
increased glutamate causes increased GABA inhibition on dopamine neurons which reduces dopamine release
what is the startle response
person is startled by an unexpected loud noise
-controls show habituation and second stimulus does not lead to startle response
-schizophrenic patients do not show habituation
what is pre pulse inhibition (PPI)
EEG measures response to a click/sound
control subjects show a lower response to the second stimulus but not schizophrenic patients
why does PPI contribute to the cholinergic hypothesis for schizophrenia
PPI is enhanced by acetylcholine receptor agonists
what ACh receptors are reduced in schizophrenia
alpha7nAChR
what is the function of neuregulin
secreted from presynaptic terminals and binds to ErbB4 receptors
required for synapse maintenance
what is the function of PSD 95
part of postsynaptic complex that keeps glutamate receptors in place
what is the function of DISC1
involved in formation of synapses
what is the function of Karilin-7
needed for synapse stabilization
what does deletion of 22q11.2 cause
deletion of two microRNAs that regulate proteins involved in spine development as well as COMT
what are typical anti-psychotics (older drugs) that treated schizophrenia
D1 antagonists
what do D2 antagonist drugs do for schizophrenic patients
treat positive symptoms but not good for negative symptoms or cognitive defects
- good to treat first psychotic episode
- lots of side effects
what are atypical anti-psychotics (newer drugs)
weaker D2 antagonists and more activity on other receptors especially 5HT
what is the mechanism of atypical antipsychotics
exert clinical effects over weeks
where was a lesion made in an animal model to reduce schizophrenic symptoms
ventral hippocampus lesion postnatal day 7
where are alpha 7 nAChRs found
presynaptic terminals
where in the brain has been found to be modulated by alpha 7 nAChRs
VTA, subthalamic nucleus, nucleus accumbens
(dopaminergic, glutamatergic, GABAergic neurons)
what kind of agonists can enhance cognition and are used in disorders like alzheimers
nicotine and cholinergic agonists
what do pre and post synaptic alpha 7 nAChRs do
pre: increase release of NT
post: depolarize neurons acting like AMPA receptors
how are NMDA receptors activated
via activation of mGlu receptors on pyramidal cells and interneurons
or
via activation of mACh receptors on GABA interneurons
how are NMDA receptors modulated
D-serine and glycine are both agonists at a co-agonist site on NMDARs
how is NMDA receptor modulation affected with schizophrenia
people with schizophrenia have lower levels of D-serine and glycine
- glycine can be increased by blocking reuptake into astrocytes with glycine transporter inhibitors
what is glutathione (GSH)
nutritional supplement that mops up ROS in cells (does not cross BBB but the precursor does and enhances the effects of anti-psychotics)
- schizophrenics have lower levels of GSH
what are stem cells
cells that can form any other cell
what is a embryonic stem cell (ES cells)
can divide indefinitely (once start differentiating, will stop dividing)
pluripotent: can give rise to all cell types
what are induced pluripotent cells (iPS cells)
cells that are introduced to 4 transcription factors to convert the somatic cell into a stem cell
what are the two layers of an ES cell in the two-layer stage
epiblast layer
hypoblast layer
what happens to the cell when the cells migrate to begin forming 3 layers
the epiblasts start migrating between the two layers to create 3 layers of cells and the hypoblasts go away
what happens after the 3 layers of the cells are formed
the body axis develops
in response to signals from the mesoderm/notochord, what do ectoderm cells divide to form
a thick neural plate
what eventually gives rise to the CNS
the neural plate
what do cells at the edges of the neuronal plate divide to form
neural crest cells
what forms the neural tube
the neural plate folds
what eventually gives rise to the PNS
the neural crest
what eventually gives rise to sensory and autonomic ganglia
neural crest cells
which part of the neural tube closes first
middle first, then the top/head side
what do cells of the neural tube give rise to
neurons
astrocytes
oligodendrocytes
what are two examples of unique markers for neural stem cells
Sox2
bHLH
what is spina bifida
incomplete closing of the neural tube that leaves a section of spinal cord and nerves exposed
- vertebra fail to develop properly and skin may fail to develop
what kind of deficiency leads to spina bifida
folic acid (vitamin B) deficiency
what determines what kind of cell the cells of the neural tube become
the position of cells within the tube
transcription factors
diffusible factors
what is neuron restrictive silencing factor (NRSF) aka REST
binds to neuron specific genes to repress them and is highest expression in areas where stem cells for non-neuronal cells are found and lowest in neuron-specific areas
(neural tube little REST - liver cells lot of REST)
what are hox genes
genes that contain highly conserved homeobox domains and express helix-loop-helix transcription factors
what does a HoxD 13 mutation cause
synpolydactyly
fusion of digits and extra digits
what does a HoxA 13 mutation cause
hand-foot-genital syndrome
- skeletal and urogenital defects
in general, are Hox gene mutations embryonic lethal
yes
what signals determine neuron identity
transcription factors
ligands and receptors
their relative concentrations (gradients)
what are the two axes of neural tube unduction
rostral to caudal
dorsal to ventral
what structures produce signals that induce cells to differentiate
roofplate
floor plate
surrounding cells
what three signals have a gradient on the rostro-caudal axis
retinoic acid
FGF
Hox genes
what three signals have a gradient on the dorso-ventral axis
BMPs secreted by ventral cells
Noggin secreted by dorsal cells
Sonic hedgehog (Shh) in dorso-ventral axis
what does retinoic acid cause
rostro-caudal axis
high concentrations form spinal cord
low concentrations form cortex
binds to nuclear retinoid receptors and acts as a transcription factor
what does a deficiency of retinoic acid cause
craniofacial abnormalities like microcephaly or cleft palate
what does BMPs cause
bone morphogenic protein - secreted by ventral cells
cause ectodermal cells to develop into skin by activation of kinases and transcription factors
what are chordin and noggin
proteins expressed by dorsal cells that bind and inhibit BMPs
where are the concentrations of BMP, chordin/noggin high
BMP high concentration in skin (ventral)
noggin/chordin high concentration in nervous system (dorsal)
default mode is to develop into nervous system so BMP can only inhibit/modify it
what is sonic hedgehog involved in
peptide that is involved in
closing of neural tube
dorso-ventral patterning
differentiation of different types of neurons
limb formation
where is there low, mid, and high concentrations of Shh in the spinal cord
low in dorsal - sensory
mid in interneurons
high in ventral - motor
what is holoprosencephaly
single lobed brain
(caused by Shh mutation)
what mutation causes basal cell carcinoma
Shh mutation
what is a meduloblastoma
lack of Shh signaling leads to uncontrolled growth in cerebellum
what side of the body does the floor plate and roof plate develop into
floor plate - ventral side of body
roof plate - dorsal side of body
what are the 6 steps of development of the CNS in order
neurulation
neuronal proliferation
neural migration
apoptosis
synaptogenesis
myelination
when does neurogenesis begin
after dorsal/ventral and rostral/caudal patterning is complete
what are 3 things that control migration
cell adhesion molecules (CAMs)
extracellular matrix (ECMs)
secreted diffusible signals modifies the actin cytoskeleton to make the cell move in desired direction
what do neuronal precursor cells migrate along
radical glia processes that span across neural tube touching both surfaces
how are layers of the cortex formed
inside out fashion
layer VI is formed first (oldest cells)
layer I is formed last (youngest cells)
what is reelin
glycoprotein that is expressed in high levels during development
- signal for neurons to jump off radical glia
- modulates synaptic plasticity
- stimulates dendrite/dendritic spine development
- regulates migration of neuroblasts in adult
what do reelin mutations cause
less white matter
enlarged ventricles
disrupted sulci and gyri
(associated with schizophrenia, bipolar, autism, alzheimers, epilepsy)
what is lissencephaly and what is it caused by
smooth brain
caused by total absence of reelin
- thick cortex and cell lamination is abnormal (cells in wrong place)
what is the order of birth for astrocytes, oligodendrocytes, and neurons
neurons
oligodendrocytes
astrocytes
once cells stop migrating, how do they define their polarity
by reorientation of the cytoskeleton
what proteins specify the axonal end of the neuronal processes
partitioning defective proteins (PAR)
- PAR mutations cause polarity to not be specified and all processes express the axonal marker tau
- mutations identified in schizophrenia
what guides the cell to the target neuronal
axonal growth cone
what are the parts of the axonal growth cone
lamellipodium - tip of the axon that is specialized to form a flat extension of microtubules
filopodia - finger-like projections containing actin fibers that protrude out and sense chemo-attractants
what influences the movement of filopodia
rapid changes in intracellular calcium that flows in through voltage gated calcium channels and TRP channels
- moves forward by actin filaments assembling and disassembling at the leading edge of the cone
what are the two main things influencing axonal growth
CAMs
diffusible factors with specific receptors
what is the difference between a tropic factor and a trophic factor
tropic: the guiding factors (chemoattractants or chemorepulsants)
trophic: support factors supporting neuronal survival
what are semaphorins
membrane-bound proteins that are cleaved to be diffusible
chemorepulsive
bind to receptors, plexin
what are slits
chemorepulsive that binds to receptor robo
what are netrins
chemoattractants
are sonic hedgehog and wnts chemotropic
yes
where do proprioceptive neurons send collaterals
to the ventral horn because they are not repulsed until the concentration of semaphorin is high
where to touch-receptive neurons send collaterals
they turn as soon as they enter the spinal cord to ascend in the dorsal horn because they are repulsed at the intermediate concentrations of semaphorins
where do temp and pain receptive neurons send their collaterals
stop growing at dorsal horn and later form synapse with spinothalamic neuron that crosses midline because they are very sensitive to low concentrations of semaphorins
how is the axon guided across the midline
the floorplate secretes netrin that attracts the axon
slit expression on the contralateral side prevents axon from turning back (has slit receptors called robo)
semaphorin gradient repels the growth cone and maintains its path
what are 4 examples are non diffusible signals for axon guidance
- ECM extracellular matrix that interact with cell-membrane bound integrins
- calcium independent cell adhesion molecules (CAMs)
- calcium dependent cell adhesion molecules (cadherins)
- ephrins and eph receptors (tyrosine kinases)
what is the difference between semaphorin in axons and semaphorin in dendrites
axons: chemo repulsive
dendrites: becomes chemo attractive due to soluble guanyl cyclase (sGC) conversion
what molecule is associated with dendritic and axonal tiling
DSCAM
down syndrome cell adhesion molecule
what does homophilic binding between DSCAMs lead to
repulsion of processes and prevention of synapses between axons and dendrites on the same neuron
what are the steps in synaptogenesis
- synaptic adhesion molecules stabilize the initial contact causing recruitment of synaptic proteins and retrograde signaling to the soma
- increased synthesis of neurotrophic factors
- presynaptic axon and cell survive if trophic factors are released
- stable synapse is maintained by synaptic activity
what are three trophic factors that are involved in synaptogenesis
NGF
BDNF
neurotrophins
what leads to differentiation of pre and post synaptic sites
signaling between inductive factors
neurexin-neuroligin interactions are essential for stable synapse formation
what are neurexins
presynaptic
localize synaptic vesicles and docking proteins
what are neuroligins
postsynaptic
affect clustering of AMPA and NMDA receptors
(can confer specificity of synapses)
what do polymorphisms in inductive factors lead to
links to autism and schizophrenia
what are three things that are necessary for formation of a synapse
contact-dependent interactions
secreted factors
signaling factors from astrocytes
what is hebbs postulate
neurons that fire together wire together
- synapses will be lost if they are not used
what is the definition of an intellectual developmental disability
intellectual disability as well as problems with adaptive behaviors
what is trisomy chromosome 21
down syndrome
what does the severity of down syndrome symptoms depend on
the amount of duplicated DNA
(not all of the chromosome needs to be present for trisomy)
what is trisomy 21 the result of
non-disjunction of chromosomes or chromatids during meiosis
- some of the expressed genes are transcription factors resulting in altered genome-wide expression
- altered methylation patterns also seen
what happens to GABA in down syndrome
increased GABAergic inhibition
what is the increased GABAergic inhibition due to in down syndrome
- changes in synapse structure in the hippocampus (synapses are larger and on shaft of axon which increases inhibitory effect)
- olig1 and olig2 transcription factors are overexpressed and drive overgrowth of GABAergic interneurons
- fewer glutamatergic synapses and they have smaller dendritic spines leading to lower activation
- overexpression of inwardly rectifying potassium channels (GIRKs)
how does overexpression of GIRKs lead to increased inhibition
gene for GIRK expressed on chromosome 21 so over expressed in down syndrome
- activation of GABA B receptors by GABA activates G proteins
- subunits of G proteins dissociate and activate potassium channels called GIRKs
- activation of the potassium channels hyperpolarizes neurons making it harder to fire action potentials - increasing the inhibition
what could be the reason for the memory and cognitive deficits in down syndrome
reduced LTP
enhances LTD
what disrupts synaptic vesicle recycling
overexpression of some genes
- will further impact LTP
what developmental pathways are disrupted in down syndrome
DOPEY2: cortical cell density - overexpression may lead to abnormal cortical lamination
SIM2: regulates sonic hedgehog expression
TPRD: growth of neurites
why is the neuron glia interaction impaired in down syndrome
S100beta
calcium binding protein secreted by glia
overexpression can lead to changes in dendritic spine density and impaired spatial learning
in mouse models, what treatments have helped to reverse symptoms of down syndrome
blocking GABA A receptors
blocking inward rectifiers
reducing copy number of olig 1 and olig 2 to restore hippocampal function
why does fragile X syndrome disproportionally affect males
it is on a X chromosome
what is fragile X syndrome caused by
deficiency or absence of fragile X messenger ribonucleoprotein 1 (FMRP)
- caused by expansion of CGG in the promoter region of FMR1 gene on X chromosome
what does the expansion of the CGG on the FMR1 gene lead to
methylation and repression of FMR1 gene transcription and FMR protein is not synthesized
what does the increased methylation of promoter due to extra repeats cause in fragile X syndrome
reduced or absent transcription
(more repeats –> more methylation –> less transcription/translation –> less protein)
what are three effects that FMRP has on brain development and function
effects every aspect
- inhibits transcription/translation of too many proteins
- alters epigenetic regulation/chromatin modification
- directly interactions with ion channels and regulates their function
what are early development consequences of FMRP deficiency
altered proliferation and differentiation of progenitor cells - increased proliferation and preferentially develop into glia
- altered development of astrocytes
- deficiencies in myelination and white matter
- synaptogenesis reduced
what are the dendrites like in fragile X syndrome
long, thin dendritic spines
smaller spine heads
increased spine density
what is the mechanism of mGluR dependent LTD
activation of mGlu receptors
Gq g proteins are activated
phospholipase c activated
mTOR and ERKs increase translation of mRNAs in dendrites
FMRPs inhibit translation
OR
endocytosis of AMPA receptors leading to reduced post synaptic activity (LTD)
what is the mechanism that causes an FMRP deficiency to increase LTD
there is no FMRP so there is more endocytosis of AMPA receptors leading to more reduction of post synaptic activity (LTD)
what are treatments for fragile X syndrome
reduce mGlu receptor expression or mGlu antagonist
GABA agonists to reduce the release of glutamate
lithium
what is rhett syndrome
x linked disorder - almost always affects girls
development normal at first then regression
loss of cognitive functions
handwringing movements
what is the cause of rhett syndrome
de novo mutation of MeCP2
what is MeCP2
nuclear protein that modulates transcription
modifies transcription of BDNF
where does the methyl binding domain of MeCP2 bind
to methylated CpG sites on DNA
what causes the genes in the region of DNA that MeCP2 binds to not be expressed
transcription repression domain (TRD) recruits corepressor proteins which results in deacetylation and condensation of chromatin which makes it not accessible to transcription machinery
in rhett syndrome, what does a lack of functional MeCP2 impair
activity-dependent release of BDNF
normally, how is BDNF synthesized
neuronal activity –> Ca influx –> activation of CamK II which phosphorylates MeCP2 –> MeCP2 dissociates and transcription activates
what are structural changes associated with MeCP2 deficiency
decreased brain volume
simpler dendrites
what functional changes are associated with MeCP2 deficiency
reduction in glutamatergic synapses
reduced LTP
reduction in NT and their functions
what are some synaptic changes in rhett syndrome
decrease in number and size of dendritic spines
decreased LTP
decreased GABAergic transmission
if the MeCP2 mutation is reversed in rhett syndrome, can the symptoms be reversed
yes
what are the changes in glia in rhett syndrome
impaired activity of microglia
thinner myelin
decreased microtubule stability
decreased expression of EAAT2
what are treatment options for rhett syndrome
replacement of bone marrow cells with cells containing normal MeCP2
restoring BDNF in brain
symptomatic treatment
what are some characteristics of autism spectrum disorder (ASD)
difficulties in social communication
restricted/repetitive behaviors and interests
hyper/hyposensitivity
language difficulties
what is different about the connectivity in ASD
hyperconnectivity between neurons of the same region
hypoconnectivity between various areas of the brain
what are many of the autism genes involved in
synapse development and maintenance
what are the changes in synaptic genes that are seen in ASD
mutations in neurexins and neuroligins
mutations in SHANK protein making post synaptic scaffold
ubiquitin ligase mutations
what are NT changes in ASD
glutamate and serotonin are increased
GABA is decreased
