Neural Circuit Refinement: Axon Pruning

• Lecture 16 focuses on refining neural circuits through axon pruning and synapse refinement.
• Regressive events like axon pruning and synapse elimination play a critical role in sculpting the developing nervous system.

Importance of Circuit Refinement

• Earlier lectures covered neuron generation, migration, and survival, but these alone are insufficient for functional neural circuits.
• The developing nervous system undergoes extensive refinement to ensure precise connectivity.
• Initial overproduction of neurons and connections is viewed as a "draft" that is pruned/refined into a mature nervous system.

Axon Pruning and Synapse Elimination

• Two key regressive events are axon pruning and synapse elimination.
• Axon pruning is the selective elimination of axon branches or collaterals, ensuring axons innervate the correct targets and form appropriate connections.
• Synapse elimination is the removal of synaptic connections between neurons, refining neural circuits by removing redundant or inappropriate synapses and strengthening connections between co-active neurons.
• Regressive events involve tightly controlled developmental processes using molecular pathways.

Refinement of Visual Circuits

• Circuit refinement principles are illustrated using the development of the mammalian visual system from the retina to the visual cortex including:
• Retinal Ganglion Cells (RGCs): Output neurons of the retina project their axons through the optic nerve to the brain.
• Lateral Geniculate Nucleus (LGN): RGC axons from each eye initially innervate overlapping regions of the LGN, a relay station in the thalamus.
• Ocular Dominance Columns (ODCs): LGN axons project to the primary visual cortex (V1), where they segregate into distinct stripes called ODCs. Each ODC receives input primarily from one eye, establishing binocular vision.
• Synapse elimination in the LGN refines this pathway with individual LGN neurons initially receiving input from multiple RGCs from both eyes
• During development, convergent input is pruned so most LGN neurons become monocular for single eye input.

Shaping Connections Through Experience

• Neuronal activity is crucial for proper circuit refinement, especially in visual system for normal ODC development.
• Monocular deprivation, closing one eye during development, disrupts ODC formation as the open eye's ODCs expand and the closed eye's ODCs shrink.
• Binocular deprivation, depriving both eyes of light, does not prevent ODC formation, suggesting spontaneous neuronal activity is enough to establish the initial framework of ODCs.

Driving Refinement in the Absence of Visual Input

• Spontaneous retinal waves are patterns of neuronal activity that propagate across the retina without visual stimulation and provide the activity to drive ODC formation.
• Blocking these waves with tetrodotoxin (TTX), a sodium channel blocker, disrupts ODC formation.

Molecular Mechanisms: Hebbian Synaptic Plasticity

• Hebbian synaptic plasticity underlies activity-dependent refinement.
• The Hebbian rule states "cells that fire together, wire together," meaning synapses between co-active neurons are strengthened, while asynchronous neurons weaken.
• Long-Term Potentiation (LTP): Co-activation of pre- and postsynaptic neurons strengthens their connection, enhancing synaptic transmission.
• Long-Term Depression (LTD): Asynchronous activity between neurons weakens their connection, reducing synaptic transmission.
• NMDA receptors (NMDARs) may play a role in Hebbian plasticity by requiring both glutamate binding and postsynaptic depolarization for activation, making them ideal coincidence detectors.

Refinement Through Elimination and Strengthening

• Regressive events, mainly axon pruning and synapse elimination, sculpt neural circuits.
• Initial overproduction of neurons and connections are followed by extensive refinement.
• Axon pruning and synapse elimination are tightly controlled developmental processes.
• Activity-dependent mechanisms, such as Hebbian synaptic plasticity, drive refinement based on neuronal activity patterns.
• Spontaneous activity, like retinal waves, plays a role when external input is absent.
• The developing visual system exemplifies these principles, with ODC formation depending on both experience and spontaneous activity.
• The developing brain undergoes construction and deconstruction, with regressive events being equally as important as progressive events.