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Research Departments > Molecular, Cellular and Developmental Neurobiology department > Axon elongation and axon initial segment function > Research Report

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Axon elongation and axon initial segment function

The proper function of neuronal physiology, and thus the functions of the nervous system depends on a high degree of morphological and functional polarization. The first step in the morphological polarization of neurons is the formation and growth of an axon to reach their targets, followed by the development of dendrites. The dendrites and axons exhibit differential expression of structural and functional proteins, allowing a vectorial transmission of information between the dendrites and the axon terminals.

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Axon growth is highly regulated by intracellular signaling pathways (eg. PI3K/Akt/GSK3) and the receptors on the neuronal membrane that positively or negatively regulate axon growth and growth cone guidance. In our laboratory we have identified several receptors that act in concert to modulate axonal growth (P2X7, P2Y1 and P2Y13).

Accompanying the axonal elongation, it is generated the Axon Initial Segment (AIS), place of action potentials generation in response to signals received by the neuron. This is possible by the high concentration of voltage-gated ion channels in a space of about 35 microns. This action potential is amplified and propagated along the axon at the nodes of Ranvier to reach the pre-synaptic region where neurotransmitters are released.

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EO

The axon initial segment is extremely important in the neuron, and neuronal physiology depends on proper function. First is where the nerve impulse is generated, and also acts as a barrier that differentiates the somato-dendritic and axonal domains controlling protein trafficking to the axon. Thus, its integrity is necessary for the regeneration of axons after injury. Its dysfunction or composition alteration is related to multiple nervous system diseases (eg, Angelman Syndrome, Alzheimer's, schizophrenia, autism etc. ..), as well as injuries due to traumatic brain damage or ischemia.

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Figure: The initial segment of the axon is a therapeutic target to protect neurons against ischemia.

In fact, the removal of AIS specific proteins happens preceding the onset of neuronal death. Recent studies in several laboratories, including our laboratory, have shown that the axon initial segment has a high degree of plasticity and can change its distance to the soma, its length, and the concentration of ion channels. These changes permit the adaptation of action potentials amplitude and its number to the signals received by neurons in physiological or pathological conditions. In particular, recent studies by our group have identified the function of kinases (GSK3), neurotransmitters (ATP) and membrane receptors (P2X7) as modulators of voltage gated sodium channels concentration in the AIS, and therefore the neuronal excitability. This has enabled us to demonstrate that the use of a P2X7 receptor antagonist protects axon initial segment generated against cerebral ischemia damage.

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Laboratory work is organized around two main research lines:

  1. Study of signaling cascades and membrane receptors that regulate the formation, elongation, and regeneration of an axon.
  2. Identification of the intracellular mechanisms and membrane receptors which modulate adaptor proteins and voltage-gated ion channels concentration at the axon initial segment, and their role in disease models and brain damage.

To address these objectives we used different experimental approaches. First, we study these mechanisms in primary cultures of hippocampal or cortical neurons that we can maintain in culture until they achieve a high degree of differentiation (1 month). We express receptors or regulatory proteins coupled to GFP using transfection or nucleofection techniques, and we analyze their influence on axonal growth, the composition of the axon initial segment and its plasticity by immunofluorescence techniques, confocal microscopy and electrophysiology. Second, we transfer these results to hippocampal slices and animal models. Finall , when it is necessary to observe the function of these proteins in the early development of the brain, we performed electroporations "in utero". This multidisciplinary approach allows us to understand the function of receptors and signaling molecules, and the identification of possible therapeutic targets and drugs of possible use in pathologies related to the axon initial segment and axon.

Relevant publications:

1) ATP-P2X7 Receptor Modulates Axon Initial Segment Composition and Function in Physiological Conditions and Brain Injury. Del Puerto A, Fronzaroli-Molinieres L, Perez-Alvarez MJ, Giraud P, Carlier E, Wandosell F, Debanne D, Garrido JJ.
Cereb Cortex. 2014 Mar 7. [Epub ahead of print]

2) GSK3 and β-catenin determines functional expression of sodium channels at the axon initial segment. Tapia M, Del Puerto A, Puime A, Sánchez-Ponce D, Fronzaroli-Molinieres L, Pallas-Bazarra N, Carlier E, Giraud P, Debanne D, Wandosell F, Garrido JJ.
Cell Mol Life Sci. 2013 Jan;70(1):105-20.

3) Adenylate cyclase 5 coordinates the action of ADP, P2Y1, P2Y13 and ATP-gated P2X7 receptors on axonal elongation. del Puerto A, Díaz-Hernández JI, Tapia M, Gomez-Villafuertes R, Benitez MJ, Zhang J, Miras-Portugal MT, Wandosell F, Díaz-Hernández M, Garrido JJ.
J Cell Sci. 2012 Jan 1;125(Pt 1):176-88. doi: 10.1242/jcs.091736. Epub 2012 Jan 16.

4) Impaired function of HDAC6 slows down axonal growth and interferes with axon initial segment development. Tapia M, Wandosell F, Garrido JJ.
PLoS One. 2010 Sep 23;5(9):e12908. doi: 10.1371/journal.pone.0012908.

5) Casein kinase 2 and microtubules control axon initial segment formation. Sanchez-Ponce D, Muñoz A, Garrido JJ.
Mol Cell Neurosci. 2011 Jan;46(1):222-34.


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