Neural tube induction, closure Neural tube induction, closure. Tube closes temporarily to allow for proliferation of telencephalon.

Just another view of neural tube closure.

Localized proliferation at subventricular zone Localized proliferation at subventricular zone. Cell division within the zone…mitosis occurs at the basal membrane.

Neurons residing in different brain regions are born at different times.

Newly born neurons migrate radially along specialized astrocytes called radial glial cells.

Laminar inside out patterning of cortex.

Use of radioactive thymidine to mark neurons born at different days.

GABAergic neurons tangential migration instead of radial.

Proliferative areas…RMS for new olfactory neurons, DG of hippocampus, and SVZ. New cells incorporated into granule cell layer of HPC. Mostly glia. Summary of the steps of cell proliferation, migration, and integration into circuits. Neurotransmitters act with hormones and trophic factors to shape development.

Gradual elaboration of dendrites, some migration of cell bodies as dendrites matures, receive signals from extrinsic environment.

When different neurotransmitter containing cells are born. Selected..

A balance of excitation and inhibition If GABA and glutamate are mis-matched, growth may not occur, or cell death could occur GABA initially excitatory GABA synapses formed first GDP (giant depolarizing potentials) form network-driven excitation, necessary for neuronal growth and synapse formation

GABA induced calcium transients mediated by L-type Ca channels GABA elicits Ca transients during development, as does glutamate agonist. Blocked by blocking L-type Ca channels. Ie. GABA must depolarize cells at this developmental stage.

Em for any given ion is the membrane potential at which forces driving the ion in and out of the cell are exactly balanced. This potential shifts to more hyperpolarized potentials for Cl- during development. Very close to resting potential means small driving force on Cl-. During development, Cl- is about 25mM inside the cell, which is sufficient to cause efflux of Cl- through GABA channels leading to depolarization.

Ben Ari Figure 1. How does the Cl- concentration reduce to its adult levels? Increasing activity of the KCC2 pumps Cl- out until the resulting intracellular concentration is about 7mM. The activity of GABA is required to turn on KCC2 expression (blocking receptors with bicuculline and picrotoxin). Tetrodotoxin blocks Na channels, had no effect on the KCC2. So the depolarizing activity of GABA itself is all that is required to induce the shift.

Sequential formation of GABA and glutamate synapses in HPC Sequential formation of GABA and glutamate synapses in HPC. Primate, in utero shown above--same as rat. Heterogeneity!! In Rat HPC, 80% are silent with no PSC, 10% are GABA only, and 10% are GABA + Glutamate PSC. Correlation with dendritic arborization. Interneurons follow a similar gradient but earlier, so that by birth only 3% are silent and most contain both GABA and Glutamate synapses.

Macaque embryos. Hippocampus, interneuron and pyramidal data shown Macaque embryos. Hippocampus, interneuron and pyramidal data shown. Not granule cells. Shortly before birth, GDPs disappear and more diversified activity is seen.

At early ages, GABA synergizes with glutamate, coordinate network activity. GABA depolarization is sufficient to remove the Mg block from NMDA receptors.

What causes first synapses to form? Give a silent neuron repeated current pulses, wait 30 minutes, begin to see spontaneous GABA induced PSCs. Plasticity of GABA synapses in developing hippocampus. LTD vs LTP depends on source of Ca and second messenger systems and the main effect is on presynaptic GABA release (increase for LTP, decrease for LTD). This is specific to depolarizing effects of immature GABA neurons and is not seen in adults.

This pattern is conserved among all animals examined This pattern is conserved among all animals examined. No exceptions have been found. Idea that the shift of GABA actions is a developmentally regulated function that signals the shift from a genetically programmed development to an activity/environment dependent maturation.

GABA regulation of its own synthesis during development GABA regulation of its own synthesis during development. Increases in Ca owing to GABA depolarization affect the expression of other genes as well, including activation of c-fos and transcription of BDNF.

GABA and BDNF feedback relationships., Muscimol is a GABA-a agonist, bicuculline is a GABA-a antagonist

GABA affects cell number GABA significantly stimulated survival of 5-HT and TH neurons but did not affect the survival of GABA neurons. The classical GABAA receptor antagonist bicuculline significantly re- duced the survival of 5-HT and TH neurons, whereas the pesticide dieldrin reduced the survival of 5-HT only. On the contrary, both GABAA antagonists significantly enhanced survival of GABA neurons. GABA completely blocked the effects of bicuculline on all three neuronal phenotypes, but did not reverse the effects of dieldrin on 5-HT and GABA neurons.

NT role in neurite outgrowth A. Inhibition of GABA reduces dendritic arborization. B. Blocking Na channels has no effect. C. development of GABAergic synapses (PSC) is dependent on activity. D. After chronic blockade of GABA receptors with bicuculline, PN day 7 slices show increased GABAergic synapses.

NT during development NT coupled to Gi, Go, Gq NT coupled to Gs Inhibit AC and/or activate PLC-b Stimulate proliferation 5-HT, adenosine, NE, and Ach NT coupled to Gs Activate AC, open VGCC Inhibit proliferation, promote differentiation Ach, DA, NE