Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes

Savvaki, Maria; Panagiotaropoulos, T; Stamatakis, Antonios; Sargiannidou, Irene; Karatzioula, Pinelopi; Watanabe, Kazutada; Stylianopoulou, Fotini; Καραγωγεωσ, Δομνα; Kleopa, Kleopas A.

doi:10.1016/j.mcn.2008.07.025

Cited by 72 publications

(91 citation statements)

References 69 publications

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“…Consistent with this study, TAG-1 knock-out mice indeed had disrupted juxtaparanodes (57). These mice also had impairment of learning and memory (57), which are usually associated with the function of hippocampus.…”

Section: Discussionsupporting

confidence: 88%

“…These mice also had impairment of learning and memory (57), which are usually associated with the function of hippocampus. A recent study suggests that only the glial TAG-1 is required for the JXP targeting of Kv1 channels (24), whereas our studies suggest the trans-homophilic interaction of TAG-1 is critical for the placement of Kv1.2 clusters on axonal membranes ( Fig.…”

Section: Discussionmentioning

confidence: 96%

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Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

2011

Journal of Biological Chemistry

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Precise localization of axonal ion channels is crucial for proper electrical and chemical functions of axons. In myelinated axons, Kv1 (Shaker) voltage-gated potassium (Kv) channels are clustered in the juxtaparanodal regions flanking the node of Ranvier. The clustering can be disrupted by deletion of various proteins in mice, including contactin-associated protein-like 2 (Caspr2) and transient axonal glycoprotein-1 (TAG-1), a glycosylphosphatidylinositol-anchored cell adhesion molecule. However, the mechanism and function of Kv1 juxtaparanodal clustering remain unclear. Here, using a new myelin coculture of hippocampal neurons and oligodendrocytes, we report that tyrosine phosphorylation plays a critical role in TAG-1-mediated clustering of axonal Kv1.2 channels. In the coculture, myelin specifically ensheathed axons but not dendrites of hippocampal neurons and clustered endogenous axonal Kv1.2 into internodes. The trans-homophilic interaction of TAG-1 was sufficient to position Kv1.2 clusters on axonal membranes in a neuron/HEK293 coculture. Mutating a tyrosine residue (Tyr 458 ) in the Kv1.2 C terminus or blocking tyrosine phosphorylation disrupted myelin-and TAG-1-mediated clustering of axonal Kv1.2. Furthermore, Kv1.2 voltage dependence and activation threshold were reduced by TAG-1 coexpression. This effect was eliminated by the Tyr 458 mutation or by cholesterol depletion. Taken together, our studies suggest that myelin regulates both trafficking and activity of Kv1 channels along hippocampal axons through TAG-1. Proper subcellular targeting of various Kv channels2 is critical for neuronal excitability and synaptic transmission. Molecular mechanisms underlying polarized axon-dendrite targeting of Kv channels have been extensively studied (1-10). In contrast, channel targeting in distinct membrane domains within axons is much less understood. Most axons in mammals are wrapped by layers of compact lipid membranes from myelinating glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system. Myelinated axons form distinct membrane domains, such as nodes of Ranvier, paranodes, and juxtaparanodal (JXP), and internodal regions (11)(12)(13)(14). In myelinated axons of both CNS and peripheral nervous system, Kv1 channels are clustered into JXP regions, controlling the fidelity of action potential conduction (11,(15)(16)(17).Based on the findings that the JXP targeting of Kv1 channels was largely eliminated in both Caspr2 (contactin-associated protein-like 2) and TAG-1 (transient axonal glycoprotein-1) knock-out mice, it was hypothesized that Caspr2 interacts with TAG-1 and clusters Kv1 channels via a PDZ domain-containing protein (18,19). Whereas Caspr2 is expressed only in neurons, TAG-1 is expressed in both neurons and myelinating glial cells (19 -21). Caspr2 has a PDZ domain ligand at its C terminus, but deleting PDZ domain-containing proteins, such as PSD-95 (postsynaptic density-95) and/or PSD-93 (postsynaptic density-93), in mice had no effect on the K...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 96%

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

2011

Journal of Biological Chemistry

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“…The motor coordination and gait abnormalities, previously described in Tag-1 Ϫ/Ϫ mice, could be related to the abnormal distribution of Kv1.1/1.2 channels in various CNS areas (Traka et al, 2003;Savvaki et al, 2008). Impaired motor activity and gait ataxia have previously been correlated with cerebellar dysfunction in other mouse models with cerebellar defects (Oliver et al, 2007).…”

Section: Discussionmentioning

confidence: 81%

“…It is vital in organizing the juxtaparanodes of myelinated fibers and it plays an important role in optic nerve structural organization (Traka et al, 2002(Traka et al, , 2003Chatzopoulou et al, 2008). The protein is also important in regulating several behavioral aspects since mice deficient for TAG-1 (Tag-1 Ϫ/Ϫ ) display behavioral deficits such as impaired learning and memory as well as sensorimotor gating and gait coordination defects (Fukamauchi et al, 2001;Savvaki et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Expression of TAG-1 in Glial Cells Is Sufficient for the Formation of the Juxtaparanodal Complex and the Phenotypic Rescue of Tag-1 Homozygous Mutants in the CNS

Savvaki¹,

Theodorakis²,

Zoupi³

et al. 2010

J. Neurosci.

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“…We have shown that homozygous mutants display a series of behavioral alterations such as learning and memory defects as well as motor coordination and balance abnormalities, resulting from the molecular disorganization of myelinated fibers (Traka et al, 2003;Savvaki et al, 2008Savvaki et al, , 2010. When the juxtaparanodal domain organization of myelinated fibers was rescued in vivo, learning and memory defects that are dependent on hippocampal function were also rescued (Savvaki et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

TAG-1 deficiency results in olfactory dysfunction due to impaired migration of mitral cells

et al. 2015

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The olfactory system provides mammals with the abilities to investigate, communicate and interact with their environment. These functions are achieved through a finely organized circuit starting from the nasal cavity, passing through the olfactory bulb and ending in various cortical areas. We show that the absence of transient axonal glycoprotein-1 (Tag1)/contactin-2 (Cntn2) in mice results in a significant and selective defect in the number of the main projection neurons in the olfactory bulb, namely the mitral cells. A subpopulation of these projection neurons is reduced in Tag1-deficient mice as a result of impaired migration. We demonstrate that the detected alterations in the number of mitral cells are well correlated with diminished odor discrimination ability and social long-term memory formation. Reduced neuronal activation in the olfactory bulb and the corresponding olfactory cortex suggest that Tag1 is crucial for the olfactory circuit formation in mice. Our results underpin the significance of a numerical defect in the mitral cell layer in the processing and integration of odorant information and subsequently in animal behavior.

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Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes

Cited by 72 publications

References 69 publications

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

The Expression of TAG-1 in Glial Cells Is Sufficient for the Formation of the Juxtaparanodal Complex and the Phenotypic Rescue of Tag-1 Homozygous Mutants in the CNS

TAG-1 deficiency results in olfactory dysfunction due to impaired migration of mitral cells

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