Tenascinr

5.1 The Tenascin Family

Tenascins are multimeric ECM glycoproteins. In vertebrates, five tenascins are found in various tissues, tenascins-C, -N, -R, -X, and -W. Of these, tenascins-C and -R are not only found in the CNS but also implicated in modulating different aspects of synaptic plasticity8,53. Structurally, tenascins-C and -R contain EGF-like repeats, fibronectin type III repeats, and a fibrinogen domain. Tenascin-R is one of major components of the perineuronal nets that surround a subset of neurons in the brain and spinal cord54. These nets - known already to Golgi and Cajal - have recently received renewed interest because of several studies suggesting that they may have inhibitory modulatory effects on regeneration and structural plasticity55,56.

5.2. Role of Tenascin-R in Formation of GABAergic Synapses

Electron microscopic analysis of tenascin-R KO mice revealed a reduction in the number of inhibitory somatic synapses on CA1 pyramidal neurons. In addition, existing synapses displayed both shorter active zones and reduced number of predocked vesicles57. Overall, there was a 30-40% decrease in the number of inhibitory active zones per unit length of pyramidal neuron. Such a dramatic decrease would be expected to have severe functional consequences and indeed, the tenascin-R KO mice showed a two-fold decrease in GABAa receptor-mediated unitary evoked inhibitory postsynaptic current (IPSC) amplitudes and increase in the number of release failures. These effects of tenascin-R deficiency on evoked release occurred with no changes in the size of spontaneous miniature IPSCs, but with changes in their frequency, indicating that the effect is likely to be presynaptic58.

5.3. Tenascin-R and GABAb Receptors

The mechanism underlying synaptogenic activity of tenascin-R possibly involves a carbohydrate HNK-1 (originally found on human natural killer cells, hence the name) carried by tenascin-R. Antibodies to this carbohydrate inhibited perisomatic IPSCs, although not dendritic IPSCs or EPSCs57. The effects of HNK-1 antibodies were blocked by antagonists to GABAB receptors and postsynaptic Kir channels coupled to these receptors. Moreover, HNK-1 was found to bind and inhibit recombinant GABAB receptors58. These data led to a model in which tenascin-R via HNK-1 inhibits postsynaptic GABAB receptor activation under normal conditions. In the tenascin-R KO animals, there is excessive activation of GABAB receptors, resulting in a postsynaptic activation of Kir channels and the accumulation of K+ in the extracellular space. This in turn may lead to a chronic depolarization of presynaptic terminals, an increase in spontaneous transmitter release, and a reduction in release probability and IPSC amplitude58. An increase in postsynaptic GABAB receptor-mediated currents in the tenascin-R KO animals supports this model56. Further pharmacological analysis or tenascin-R KO may help to verify whether tenascin-R regulates the number of inhibitory synapses via activation of postsynaptic GABAB receptors.

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