Neuronal Proliferation

• Overview
  • Occurs primarily within the ventricular zones (VZ) lining the neural tube.
  • Additional proliferation at secondary germinal zones:
    • Subventricular zone (SVZ) (telencephalon)
    • External granular layer (EGL) (cerebellum)
• Primary Neuroproliferative Regions
  • Dorsal telencephalon (Pallium):
    • Generates excitatory (glutamatergic pyramidal) neurons for cerebral cortex.
  • Ventral telencephalon (Subpallium):
  • Forms ganglionic eminences:
    • Lateral ganglionic eminence (LGE) → caudate nucleus, putamen
    • Medial ganglionic eminence (MGE) → globus pallidus
      • Generates inhibitory (GABA-ergic) interneurons.

• Secondary Proliferation: Subventricular Zone (SVZ)
  • Formed by cells migrating from ventricular zone.
  • Major source of later-born neurons (especially superficial cortical layers).
  • Produces neurons, astrocytes, oligodendrocytes, and maintains stem cell populations postnatally.
• Types of Cellular Proliferation
  • Asymmetrical proliferation:
    • One daughter cell remains progenitor; other differentiates into neuron/glia.
  • Radial glial cells:
    • Generate intermediate progenitors migrating to SVZ.
    • Important for generating superficial cortical layers.

Neuronal Migration

• Overview
• Neurons migrate from proliferative zones to final cortical positions.
• Guided by molecular signals (glycoproteins) interacting with neuronal cell surface receptors.
• Migration modes:
  • Gliophilic migration: guided by radial glial fibers (radial migration).
  • Neurophilic migration: guided by neuronal axons (tangential migration).
  • Vasophilic migration: recently described, guided along blood vessels.
• Radial Migration
• Early phase (somal translocation):
  • Neuron connects ventricular and pial surfaces; nucleus moves outward.
• Later phase (glial-guided migration):
  • Radial glial cells guide neurons radially outward into cortical plate.
• Critical regions involved:
  • Preplate splits into marginal zone (Cajal-Retzius cells) and subplate.
• Tangential Migration
• Primary mode for inhibitory interneurons.
• Originates in ventral ganglionic eminences (MGE, LGE).
• Interneurons migrate tangentially through SVZ, intermediate, marginal zones before radial ascent to cortex.

Cortical Organisation

• Overview
• After neuronal migration (~20–24 weeks), cortical layers form distinct lamination pattern:
  • Ventricular zone, SVZ, intermediate zone, subplate zone, cortical plate, marginal zone.
• Major third-trimester brain growth (50% cortical volume increase in last 6 weeks).
• Role of Subplate Zone
• Transient neuronal layer; peaks at 22–34 weeks gestation.
• Crucial for:
  • Early synaptic development and axonal connectivity.
  • Initial synaptic contact between thalamocortical afferents and cortical neurons.
• Rapid regression after 27 weeks gestation; apoptosis removes ~90% subplate neurons postnatally.
• Residual subplate persists longest in gyral crests (associative cortical areas).
• Thalamocortical Connectivity Timeline
• 24–25 weeks: Thalamocortical axons reside in subplate, begin entering cortical plate.
• 26–28 weeks: Formation of first synapses in cortical layers III and IV.
• 31–33 weeks: Established thalamocortical-cortical layer IV connectivity; sensory-driven functional maturation begins.
• 35–37 weeks: Inter- and intra-hemispheric connectivity expands rapidly, major changes in electrocortical activity.
• 38 weeks: Mature long-range cortico-cortical (callosal) connectivity established.

Synaptogenesis and Apoptosis

• Synapse Formation
• Region-specific temporal differences in synaptic density:
  1. Brainstem/cerebellum: earliest synapse formation and pruning.
  2. Hippocampus/posterior neocortex: follows cerebellum.
  3. Frontal cortex: latest, extends postnatally.
• Initial synapses form at 12–14 weeks gestation (preplate neurons).
• Synaptic pruning (apoptosis) shapes cortical connectivity postnatally.
• Apoptosis (Programmed Cell Death)
• Critical for proper morphogenesis and progenitor regulation.
• Energy-dependent, essential for normal development.
• Active in transient embryonic structures (e.g., subplate neurons).
• Timeline:
  • 6–7 weeks gestation: active in ventricular zone and preplate.
  • 11 weeks gestation: present in all cortical layers, maximal in proliferative zones.
  • 12–22 weeks gestation: apoptosis peaks throughout telencephalon.
• Failure in normal apoptosis → excessive neural tissue and structural anomalies.

Clinical Implications of Developmental Disruptions

• Disorders of Proliferation and Migration
• Disorders caused by abnormal neuronal proliferation or migration:
  • Cortical dysplasia
  • Lissencephaly
  • Heterotopias (subplate/intermediate zone)
  • Polymicrogyria
  • Disorders of interneuron migration associated with epilepsy and cognitive impairments.
• Disorders of Cortical Organisation
• Disrupted synaptogenesis or apoptosis leads to:
  • Neurodevelopmental delay.
  • Intellectual disability.
  • Epilepsy.
  • Autism spectrum disorders.

Summary Table: Neurodevelopmental Events

• Event	Gestational Age (weeks)	Significance / Clinical Correlates
  Primary proliferation	6–12	Formation of primary neuronal populations
  Secondary proliferation	12–20+	Superficial cortical layer formation
  Radial migration	8–24	Formation of cortical layers
  Tangential migration	8–24	Interneurons integration, epilepsy disorders
  Cortical plate formation	~20–24	Cortical layering and functional maturation
  Subplate activity peak	22–34	Critical connectivity (thalamocortical)
  Synaptogenesis peak	Region-specific (12 wks–postnatal)	Functional circuitry establishment
  Apoptosis peak	6–22	Structural refinement, prevent overgrowth

Clinical Recommendations

• Understanding timing of these events assists prenatal diagnosis, prognostication, and counseling.
• Fetal MRI valuable for assessing migration/proliferation disorders.