Module 2 Neurobiology and Development Flashcards
neural tube closure points
- Hindbrain neuropore
- Anterior neuropore (anencephaly)
- Posterior neuropore (Spina bifida)
convergent extension
extension of the embryo
Wnt activation of the planar cell polarity (PCP) pathway, Rho GTPases
folic acid
involved in:
- psychiatric/mood through TH
- Ado-Met major methyl donor for epigenetics, protein and lipid methylation
- nucleotide synthesis (purine synthesis, pyramidine reclamation)
- cell proliferation
mouse models of NTDs
crooked tail (Wnt signaling through LRP6) loop tail (convergent extension defects)
body plan (drosophila)
maternal effect genes (establishes polarity), gap genes, pair-rule genes, segmentation genes, homeotic genes (identity)
dorsal-ventral gradient
sonic hedgehog from floor plate, BMP from roof plate
microcephaly
altered balance between proliferation and apoptosis
cell cycle:
-G1-cyclin D1/D2/D3 regulation of length of G1, longer G1=more likely to leave and become neuron
-G2-M: genes target ATR/PCNT related to centrosome (downstream of RhoA)
interkinetic nuclear migration
progenitor cells only divide at the vz surface because that’s where the centrosome is, they’re anchored to the vz surface so the nucleus moves down to the centrosome when in the M phase
- otherwise microcephaly
- neurons born together migrate to the same layer
symmetric proliferation
amplify stem cells to make large progenitor pool, expansion of surface
asymmetric proliferation
neurogenesis, radial glial cells start to make both neurons and progenitors
gliogenesis
birth of astrocytes and oligodendrocytes, happens last, migrate along radial glia fibers
migration patterns
radial migration (excitatory-from vz zone of local cortex), tangential migration (inhibitory-from CGE/MGE), rostral migration (to olfactory bulb, no radial glia, slide along axons)
somatic translocation
leading process grabs onto the pial surface and pulls cell body, happens after locomotion
locomotion
glia-guided migration (dominant form of migration in cortex)
- centrosome moves forward
- nucleus moves forward (surrounded by microtubules that the centrosome pulls forward)
laminar strucure
the 6 layers in the cortex, develop “inside-out” where the deep layers are formed first then later born neurons stack on top. correlation between birth date and function (early=more cortical-subcortical projections, late=cortical-cortical projections)
functional columns
orthagonal organization, microcircuitry between superficial and deep layers in the columns. repetitive columns process defined input for specialized function
name them transcription factors
pax6 (excitatory cortex), nkx2.1 (inhibitory cortex), atoh1 (excitatory rhombic lip), ascl1/nestin (inhibitory, cerebellar vz), Otx2 (forebrain and midbrain), Gbx2 (hindbrain and spinal cord), En1 (midbrain and rhombomere 1), hox genes (rhombomeres)
(inducible) fate mapping
promoter for cell-type specific expression of cre with lsl-lacz, gets spatial lineage. if cre-ert2 then also temporal specificity
isthmic organizer
sets up compartment border, main one is fgf8. splits up otx2 and gbx2 expression to separate hindbrain from midbrain. fgf8 also found in other regions but that’s the main one. gradient of fgf8 leads to differentiation between superior and inferior colliculus
excitatory cerebellar cell birthdays
cerebellar nuclei e10.5-12.5, precursor granule cells e12.5-17.5, unipolar brush cells e14.5-17.5. target neurons made first
3 aspects regulated in development
morphology and cytoarchitecture (cell number type, migration), circuit topography (axon projections and synaptic partners), gene expression (spatial and cell-type specific expression)
cytoskeletal functions
- structure and support
- intracellular transport
- contractility and motility
- spatial organization
polarization
one side of the neuron has dendrites (the leading process) the other has an axon (trailing edge-whichever process has the greatest amount of cdc42)
actin master regulators
RhoA (downregulation leads to neurite growth)
CDC42-promotes stabilization of microtubules
Rac1-microtubule capture by advancing neurite tip, promotes growth
growth cone
filled with actin network. microtubule tips project from c-domain (central) to p-domain (front) and terminate in actin network. actin pushes membrane and microtubules invade.
- myosin2 pulls actin backwards, polymerization of actin pushes forward
- stepwise advancement in response to attractant/repulsive cues, retrograde slows, traction from clutch linked to filaments pulls the growth cone forward
microtubules
polymers of alpha and beta dimers, plus end (towards growth cone) and minus end (towards cell body). subunits added only to the plus ends.
- organizing centers (neurons have multiple) attaches to the minus end, has gamma tubulin and the dimers bind to GTP and as the microtubule grows GTP is hydrolyzed to GDP (so more GDP at the minus end)
- PTMs to the subunits microtubules give it unique properties
catastrophe
rapid polymer depolymerization, if the plus end isn’t capped and GDP catches up, the it all falls apart
kinesin
moves cargo towards the plus end (anterograde transport)
dynein
moves cargo towards the minus end (retrograde transport), transports trophic support from target neurons back to the soma
treadmilling
monomeric actin binds to ATP and gets incorporated into f-actin on the barbed end then ATP is hydrolyzed and the actin detaches from the pointed end via ADF/cofilin to give it back to the barbed end
actin branching
extracellular signals activate n-wasp which activates Arp2/3 which enucleates and creates a new actin branch, this is what pushes the membrane forward
families of guidance cues and their receptors
netrins & DCC (attract and repel, secreted), slits & robo (mostly repel, secreted), semaphorins & plexin (mostly repels, secreted and anchored), ephrins & Eph (mostly repels, anchored)
netrin /slit at the floor plate
netrin attracts the commissural axons with the DCC receptor activation of the n-wasp signaling. once they’ve crossed, they start expressing robo receptors and become repelled by the slit secreted at the midline so they don’t cross again. ipsilateral axons constitutively express robo receptors
criteria for neurotransmitters
- precursor/synthesis enzymes in the presynaptic side of the synapse
- chemical present in the presynaptic neuron
- sufficient quantity in the presynaptic neuron to have an effect on the postsynaptic neuron
- it can bind to receptors on the postsynaptic neuron
- there’s a mechanism for inactivation present
interneurons on postsynaptic neurons
modify firing frequency and the number of action potentials. graded response on target (shunting and ipscs). feed-forward and feedback inhibition, disregulation=overexcitation and seizures/excitotoxicity
interneuron classification
morphology-input/output
biochemical diversity-expression, parvalbumin and somatostatin, CR whatever that stands for
firing patterns-fast spiking, burst, etc.
homeostatic functions of astrocytes
molecular homeostasis (ions, NTs, and pH), systemic homeostasis (glucose sensing, regulation of energy balance and food intake), organ homeostasis (control over BBB), metabolic homeostasis (neurovascular coupling, regulation of local blood flow, metabolic support, glycogen synthesis and storage), cellular and network homeostasis
calcium signaling in astrocytes
from neurotransmitter receptor activation, leads to NT release, vasodilation, Ca2+ wave propagation. ER stores in soma through IP3 receptors and Ca2+ channels in processes
astrocyte-neuron lactate shuttle
provides neurons with lactate from glucose that it picked up in the blood. Neurons then convert it to pyruvate and throws it into the TCA cycle in the mitochondria to get ATP
astrocytosis
astrocytes become reactive in response to injury, increase GFAP expression, proliferate more, and form a glial scar
BBB properties
- specialized tight junctions
- suppressed transcytosis
- transporters (specific peptides, nutrients, ABC, and lipophilic agents
BBB at capillaries
endothelial cells around the vessels with tight junctions, pericytes, and astrocytic endfeet
pericytes
cells embedded in the vascular basement membrane, in microvessels (capillaries, terminal arterioles), regulate the blood brain barrier (sometimes?). inhibition of lrp1 by apoe4 from astrocytes inhibits nf-kb and leads to degradation of BBB
penetrating arteries
endothelial cells, smooth muscle cells, perivascular space with perivascular macrophages, and astrocytic endfeet
intraparenchymal arterioles
endothelial cells, smooth muscle cells, astrocytes
neurovascular coupling (functional hyperemia)
activity of the brain is linked to local circulation and increases in neuronal firing rapidly trigger vasodilation of small vessels at the site of neuronal activity. match metabolic needs with CBF
-at the capillaries its the release of potassium from the neurons picked up by astrocytes and given to pericytes and endothelial cells. endothelial cells propagate this signal
smooth muscle cells
these are the ones that undergo vasodilation induced by neuronal activity and contraction
endothelial cells
propagate hyperpolarization through gap junctions up to the smooth muscle cells to increase local blood flow
