Pinceau Organization in the Cerebellum Requires Distinct Functions of Neurofascin in Purkinje and Basket Neurons during Postnatal Development

Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2012; 32(14):4724-42. DOI: 10.1523/JNEUROSCI.5602-11.2012
Source: PubMed

ABSTRACT Basket axon collaterals synapse onto the Purkinje soma/axon initial segment (AIS) area to form specialized structures, the pinceau, which are critical for normal cerebellar function. Mechanistic details of how the pinceau become organized during cerebellar development are poorly understood. Loss of cytoskeletal adaptor protein Ankyrin G (AnkG) results in mislocalization of the cell adhesion molecule Neurofascin (Nfasc) at the Purkinje AIS and abnormal organization of the pinceau. Loss of Nfasc in adult Purkinje neurons leads to slow disorganization of the Purkinje AIS and pinceau morphology. Here, we used mouse conditional knock-out techniques to show that selective loss of Nfasc, specifically in Purkinje neurons during early development, prevented maturation of the AIS and resulted in loss of Purkinje neuron spontaneous activity and pinceau disorganization. Loss of Nfasc in both Purkinje and basket neurons caused abnormal basket axon collateral branching and targeting to Purkinje soma/AIS, leading to extensive pinceau disorganization, Purkinje neuron degeneration, and severe ataxia. Our studies reveal that the Purkinje Nfasc is required for AIS maturation and for maintaining stable contacts between basket axon terminals and the Purkinje AIS during pinceau organization, while the basket neuron Nfasc in combination with Purkinje Nfasc is required for proper basket axon collateral outgrowth and targeting to Purkinje soma/AIS. Thus, cerebellar pinceau organization requires coordinated mechanisms involving specific Nfasc functions in both Purkinje and basket neurons.

    • "Interaction partners of neurofascin at the AIS are represented by components of the extracellular matrix including tenascin-R and brevican (Hedstrom et al. 2007; Bruckner et al. 2006; Volkmer et al. 1998). Alternatively, neurofascin may homophilically interact with neurofascin as suggested for basket cell terminals (Buttermore et al. 2012; Pruss et al. 2004). NF186 was also discussed to contribute to the stabilisation of nodal complexes. "
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    ABSTRACT: The neuronal cell adhesion molecule neurofascin is expressed in highly complex temporally and spatially regulated patterns. Accordingly, many different functions have been described including control of neurite outgrowth, clustering of protein complexes at the axon initial segments as well as at the nodes of Ranvier and axoglial contact formation at paranodal segments. At the molecular level, neurofascin provides a link between extracellular interactions of many different interaction partners and cytoskeletal components or signal transduction. Such interactions are subject to intimate regulation by alternative splicing and posttranslational modification. The versatile functional aspects of neurofascin interactions pose it at a central position for the shaping and maintenance of neural circuitry and synaptic contacts which are implicated in nervous system disorders.
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    • "Although the mechanisms responsible for this decrease in GABA transmission have not been elucidated, another article noted a decrease in AnkG in the superficial cortical layers of schizophrenic patients (Cruz et al., 2009). As previously stated, a decrease in AnkG disrupts localization of AIS components , including Nfasc, and disruption of Nfasc alters GABA receptor clustering and targeting of GABAergic synapses to the AIS (Ango et al., 2004; Burkarth et al., 2007; Cruz et al., 2009; Buttermore et al., 2012). Therefore , it is possible that alterations in AIS stability and function may create an imbalance of neuronal activity that is observed in schizophrenic patients. "
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