1126224 lecture

Recap

Permissive Signals for Axon Outgrowth

  • Originate from:

    • Extracellular matrix

    • Other axons

    • Other cells long distances away

  • Tend to be chemoattractants or chemorepellents (Lowery and Van Vactor 2009)

Integrin Receptors

  • Integrin receptors bind to laminin and fibronectin to transduce signals

    • Located on growth cone membrane: alpha and beta integrin receptors

    • Form heterodimers (1 alpha + 1 beta)

    • 24 heterodimers possible in human neurons

    • Highest expression during brain development

    • Decline in mature brain

    • Promotes axon extension in neurons unable to extend neurites typically (Myers et al. 2001)

Upstream Factors

  • Internal factors regulate integrin receptor function

    • Example: Talin

      • Binds to beta subunit of integrin receptors

      • Loss of Talin prevents integrin activation

      • Alters angle of transmembrane segment necessary for ligand binding (laminin/fibronectin)

Downstream Factors

  • Example: Vinculin and Paxillin

    • Focal adhesion proteins involved in linking actin filaments and integrin receptors

    • Establish a physical link between extracellular matrix (laminin) and actin

Axon Outgrowth Facilitation

  • Growth cone advance can be facilitated by fasciculation

    • Fasciculation: adhesion of axons together

    • Caused by surface cell adhesion molecules (CAMs)

      • Examples: cadherins, dscams

Pioneer Axons as Scaffolds

  • Pioneer axons provide a scaffold for follower axon extension

    • Support organizational structure for further axonal growth

Cell Adhesion Molecules (CAMs)

  • Diversity in the nervous system

  • Important in synapse formation and stabilization (Moreland and Poulain 2022)

Regulation of Axon Fasciculation

  • Fasciculation involves tight interactions between axons

    • Homotypic interactions: interactions between the same CAMs

    • Heterotypic interactions: between different CAMs

    • Same proteins can exhibit different interaction types (e.g., L1CAM)

L1CAM and Abnormal Motor Innervation

  • L1CAM inactivation disrupts muscle innervation

    • Blocking L1CAM in chick muscle results in nerve sprouting (Landmesser et al. 1988)

NCAM and Retinal Axon Pathfinding

  • Loss of NCAM causes abnormal axon pathfinding in chicken embryo retina (Thanos et al 1984)

    • Results in misrouting in the retina and affects axon fasciculation in tectum

Cadherins in Axon Fasciculation

  • Protocadherin17 (pcdh17) critical for homotypic fasciculation of amygdala axons extending to hypothalamus and ventral striatum

    • Loss of Pcdh17 leads to impaired axonal growth (Hayashi et al. 2014)

Pcdh17 and Actin Regulation

  • Pcdh17 interacts with actin affecting growth cone interactions and outgrowth through associated proteins (Ena/VASP, Lamellipodin)

Axon Guidance Cues

  • Govern targeted axon outgrowth through:

    • Cell-cell contacts

    • Adhesion proteins

    • Extracellular matrix proteins and receptors

    • Chemoattractants and chemorepellents

Synapse Formation in the CNS

  • Pre- and post-synaptic specializations occur at active contact sites

    • Dendritic filopodia contact axons and recruit synaptic vesicles

Neuromuscular Junction (NMJ) Formation

  • Involves axon termination, muscle, and basal lamina interactions

    • Motor neuron axon secretes agrin into the basal lamina

    • Agrin signals muscle through MuSK, resulting in clustering of acetylcholine receptors

    • MuSK activates Rapsyn

    • MuSK and Rapsyn together clutter Acetylcholine receptors into plaques

Reciprocal Signaling in NMJ Formation

  • Basal lamina facilitates calcium influx into axon terminals, enhancing neurotransmitter release

  • Promotes positive feedback in synapse formation

Critical Periods in Development

  • Allows for modifications in innervation patterns

  • After certain developmental stages, large-scale modifications cease

Ocular Dominance Columns

  • Discovery by Hubel and Wiesel demonstrating eye-specific innervation patterns in the visual cortex

    • Altered by visual input; permanently closing one eye leads to reduced activity in that eye's columns

Types of Synaptic Refinement

Changes in Synaptic Capacity

  • Involves alterations in the strength or number of synapses between neurons, allowing for precise modulation of neural circuits over time.

  • Example: Neuromuscular Junction (NMJ)

    • Maturation process refines the connections made by motor neurons from innervating multiple muscle fibers to targeting a single muscle fiber.

    • This refinement is crucial for enhancing the precision of muscle contractions and overall motor control.

    • Mechanism: It requires muscle activity for synaptic loss, indicating that active use of muscle fibers influences which synaptic connections are retained or eliminated.

Synaptic Rearrangement

  • Involves the reorganization of existing synaptic contacts, allowing for a more efficient neural network as the organism learns or adapts to new experiences.

  • This process can be influenced by environmental factors and experiences, leading to lasting changes in how neurons communicate.

Synaptic Segregation

  • Refers to the process whereby different types of synaptic inputs are separated spatially or functionally, permitting more specialized neuronal functions.

  • This segregation allows for distinct pathways and information processing for various sensory modalities or motor tasks.

Programmed Cell Death

  • Also known as apoptosis, this process is critical for eliminating excess neurons and synapses during development, thereby refining neural circuits.

  • Ensures that only the most effective and pertinent connections remain, enhancing the efficiency of communication in the nervous system.

Synaptic Communication Mechanisms

  • Involves a variety of neurotransmitter receptors that play critical roles in mediating synaptic transmission.

  • Receptor Types: Ionotropic glutamate receptors, particularly AMPA and NMDA receptors, are fundamental in the process of synaptic plasticity.

  • AMPA Receptors: Responsible for fast synaptic transmission, their activity facilitates the rapid depolarization of the neuron's postsynaptic membrane.

  • NMDA Receptors: Unique in that they require both ligand binding and a postsynaptic depolarization to open, allowing calcium ions to flow into the neuron. This calcium influx is crucial for initiating signaling cascades involved in long-term potentiation (LTP) and long-term depression (LTD), which are essential mechanisms for learning and memory.

  • LTP is characterized by an increase in AMPA receptor clustering at the synapse, strengthening synaptic transmission, while LTD involves a decrease in AMPA receptor activity following inactivity, promoting synaptic pruning.

Long-Term Potentiation (LTP) and Long-Term Depression (LTD)

  • LTP results from increased AMPA receptor clustering; LTD involves reduced activity of AMPA receptors after inactivity

Neurons and Hebbian Synapses

  • Neurons strengthen connections by coordinating firing; important for learning and memory processes

The Role of Critical Periods in Development

  • Mark periods for maximum plasticity in synaptic connections

  • Impact on axon growth and synaptic maturation processes

Factors Influencing Critical Period Endings

  • Includes cessation of axon growth, maturation of synaptic transmission, and constraints on cortical activation

  • Astrocytes may also regulate the closing of critical periods.