Ontogenesis in the CNS – Neurogenesis During Embryonic Development Formation of the Neural Tube Neural Groove Neural Plate

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Ontogenesis in the CNS – neurogenesis during embryonic development Formation of the neural tube neural groove neural plate

neural groove

neural crest

notochord neural tube The developing neuroepithelium

ventricular zone (pseudostratified epithelium) Interkinetic nuclear migration within the ventricular basal (pial)

zone surface

cilium ventricular zone ventricular apical (ventricular) surface • neuroepithel stem cell [NE (stem) cell] Tsai et al., Nat Neurosci. 2010 Dec;13(12):1463-71 - radial shape, anchored to pial and ventricular ECM; ventricular cilium - centrosome localized near the cilium, microtubule + end towards the pia - nuclear movement based on dynein / kinesin (KIF1A) activity along cell cycle - apical mitosis: symmetric cell divisions, expansion in cell number/surface Interkinetic nuclear migration within the ventricular zone Interkinetic nuclear migration within the ventricular zone Noctor et al.

• neuroepithel stem cell [NE (stem) cell; NEC] -> radial glia - radial shape, anchored to pial and ventricular ECM; ventricular cilium - centrosome localized near the cilium, microtubule + end towards the pia - nuclear movement based on dynein / kinesin (KIF1A) activity along cell cycle - apical mitosis: symmetric / asymmetric cell divisions The radial glia (RG)

VZ: ventricular zone PP: preplate migráló neuronális prekurzorok SVZ: subventricular zone CP: cortical plate IZ: intermedier zone MZ: marginal zone SP: subplate radiális glia

E30 E31-32 E45 E55 14w (human) Bystron et al; Nat Rev Neurosci. 2008 Feb;9(2):110-22.

Rakic P. J. Comp. Neurol. 1972, 145: 61-84

• originally: radial migratory „railway” from the VZ towards the pial surface in the neocortex • transient phenotype, develops into astrocytes

„protomap” hypothesis (Rakic) The radial glia (RG) • transition from NECs, transient neuronal stem cells • nestin+; glial features (GLAST, S100, GFAP, vimentin, BLBP) • direct and indirect (via basal progenitors / transient amplifying cells / neuronal precursors / neuronal progenitors) ways of generating neurons – neurogenic phase • perinatally gliogenic phase: formation of astrocytes / oligodendrocytes

(

IP: intermedier progenitor = basal progenitor = transit amplifying cell = neuronal progenitor = neuronal precursor (NPC) Factors influencing RG’s fate proliferative effect [Ca2+] Wnt / Shh / Par signaling Notch-Delta synchronisation IC

retinoids differentiation GABA, Glu GABA, (Glu)

Elias, Kriegstein

CNTF/LIF; TGFb Morphogenes influencing cortical neurogenesis Morphogenes influencing cortical neurogenesis Environmental clues influencing cortical neurogenesis Adult neurogenesis a long story.... dogma: no neurogenesis within the adult brain 50's: 3H-timidin labeling to mark dividing cells in vivo within the brain 60's, Altman: newborn neurons within the rodent neocortex, dentate gyrus (DG) and in the olfactory bulb

70-80's, Kaplan: new neurons within the hippocampus survive for many years and form functional circuits 80's: functional neurogenesis is required for learning new songs (high vocal center), (Nottebohm) 1992: neurosphere and NSCs isolated from adult rodent brain (Reynolds, Weiss) 1999: neurosphere and NSCs isolated from adult human brain (Kukekov) 2000- thousands of papers....

1999-2004: who is the neural stem cell??? -> GFAP+ glia cell Neurogenesis within the adult brain songbirds: mammals: hippocampus dentate high vocal center (striatum) subventricular zone gyrus (GD) (SVZ) subgranular zone (SGZ)

Alvarez-Buylla and Garcı´a-Verdugo J. Neurosci., 2002, 22(3):629–634

Nottebohm J. Neurosci., 2002, 22(3):624–628 GABAergic inhibitory granule GD Glu-ergic cells; dopaminergic periglomerular granule cells cells in the olfactory bulb Neurogenesis within the adult brain

BrdU+ cells Neurogenesis within the adult brain Adult neural stem cells within the SVZ SVZ: astrocyte B cell [radial glia-like cell]: self-renewing, GFAP + one (or more) cilium towards the lumen

C cell: fast division, transient amplifying cell

A cell: committed, migrating neuroblast

ependyma: noggin production Nat Rev Neurosci 2003 6 1127 (niche); cilia • in vivo: only OB neurogenesis • in vitro multipotency: neuron, oligodendroglia, astrocyte can be formed

• differentiation is determined by the local micro-environment (niche) Adult neural stem cells within the SVZ RMS: neuronal chain migration RMS: rostral migratory stream • chain migration of interneurons - PSA-NCAM, EphB2 / ephrin-B2, neuregulin / Erb4 • within the OB (olfactory bulb), radial migration starts (reelin) SVZ neurogenesis – integration of new neurons neurogenesis within the olfactory system: • central: (accessory) olfactory bulb - granule cell - periglomerular cell

• periphery: vomeronasal organ - sensory neurons SVZ neurogenesis – integration of new neurons SVZ neurogenesis – integration of new neurons

AOB: accessory olfactory bulb; DG: dentate gyrus; LV: lateral ventricle; MOB: main olfactory bulb; MOE: main olfactory epithelium; RMS: rostral migratory stream; dendro-dendritic VNO: vomeronasal organ synapses OSN: olfactory sensory neuron PG: periglomerular neuron GC: granule cell (szemcsesejt) MC: mitral cell • constant supply of new neurons: - OSN: derived from MOE precursors, axons are projected into the glomeruli; same receptor – same glomerulus - PG: dendro-dendritic synapses formed on the mitral cells - GC: recurrent dendro-dendritic synapses on the lateral dendrites of the mitral neurons (lack of axons) Neurogenesis within the adult SVZ Neurogenesis within the adult SVZ Functional importance of SVZ neurogenesis

• daily replacement of 1% of neurons within the OB (~97% granule cells)

• critical period for survival between 2-6 weeks (half of new neurons die)

• constant turnover of sensory neurons -> constant turnover of interneurons within the (A)OB (new neurons should integrate into the network)

• new neurons: strong inhibitory effects on the glomeruli (PG neurons) or on the mitral/tufted cells (granule cells)

• local networks: processing olfactory stimuli depending on memory, pregnancy, behavior... Adult neural stem cells within the SGZ

SGZ: astrocyte Alvarez-Buylla*, A. Lim Neuron, Vol. 41, 683–686, 2004,

Doetsch F. Nat Neurosci 20036 1127

B cell (radial astrocyte, type 1 cell): self-renewal, GFAP +

D cell (type 2 cell): neuronal progenitor (neuroblast)

G cell: granule cell

GD granule neuron: mature Glu-ergic interneuron Adult neural stem cells within the SGZ

• radial astrocytes (B cells) are directly derived from radial glia (?) Adult neural stem cells within the SGZ Integration on newly born SGZ neurons Integration on newly born SGZ neurons

• no synaptic inputs during the first week for young GCs, only tonic GABA activation + slow maturation - - GABAA receptors; high [Cl ]IC -> depolarizing action of tonically released GABA - neuronal activity starts ~3w - hyperpolarizing GABA activity develops around 4w - Gluergic inputs develop later - increased activity- dependent synaptic plasticity during maturation Integration on newly born SGZ neurons Neurogenesis within the adult SGZ Neurogenesis within the adult SGZ Functional role of new SGZ neurons

• morphological and electrophysiological maturation (~4-6 weeks)

• spatial memory, explicit learning – responsible for pattern separation • malfunctioning leads to pathological brain functions (can be a cause and a consequence, as well): - epilepsy - depression, anxiety - stress

• new neurons: activation of local interneurons -> strong inhibition at the network level; during maturation, increased sensitivity to activity-dependent plasticity Glial-neuronal transition during adult neurogenesis Neurogenesis within the CNS

Solid arrows are supported by experimental evidence; dashed arrows are hypothetical. Colors depict symmetric, asymmetric, or direct transformation. IPC, intermediate progenitor cell; MA, mantle; MZ, marginal zone; NE, neuroepithelium; nIPC, neurogenic progenitor cell; oIPC, oligodendrocytic progenitor cell; RG, radial glia; SVZ, subventricular zone; VZ, ventricular zone. Neurogenesis within the CNS Lineage tree of neural stem cells Lineage tree of neural stem cells Essay questions Describe the cellular composition of the ventricular zone (VZ)! Explain the functional importance of VZ cells in respect to neurogenesis! / Hogyan épül fel az embrionális ventrikuláris zóna (VZ)? Milyen sejt(ek) alkotjá(k)? Milyen szerepet tölt be a VZ az idegrendszer fejlődése során? What kind of role do radial glial cells play in neurogenesis? Where and when can they be found within the CNS? What kind of factors regulate their proliferation and differentiation? / Hol található meg és milyen tulajdonságokkal, markerekkel jellemezhető a radiális glia? Milyen szerepet tölt be az idegrendszer fejlődése során? Milyen faktorok irányítják a proliferációjukat, illetve az elköteleződési lépéseket? Where does neurogenesis take place in the adult CNS? Give a brief overview of the newly born neurons! Explain their functional importance! / Hol keletkeznek új idegsejtek a felnőtt idegrendszerben? Hol és milyen szerepet töltenek be az újonnan képződő idegsejtek? Compare the characteristics (similarities and differences) between the steps of adult neurogenesis within the SVZ and SGZ! / Hasonlítsa össze az SVZ-ben és az SGZ-ben folyó felnőttkori neurogenezis főbb sajátságait (hasonlóságait és a különbségeket)! Recommended literature