F3/Contactin promotes hippocampal neurogenesis, synaptic plasticity, and memory in adult mice

Abstract

F3/contactin, a cell-adhesion molecule belonging to the immunoglobulin supergene family, is involved in several aspects of neural development including synapse building, maintenance and functioning. Here, we examine F3/contactin function in adult hippocampal neurogenesis, synaptic plasticity, and memory, using as a model TAG/F3 transgenic mice, where F3/contactin overexpression was induced under control of regulatory sequences from the human TAG-1 (TAX-1) gene. Transgenic mice aged 5 (M5) and 12 (M12) months exhibited an increase in hippocampal size, which correlated with positive effects on precursor proliferation and NeuN expression, these data suggesting a possible role for F3/contactin in promoting adult hippocampal neurogenesis. On the functional level, TAG/F3 mice exhibited increased CA1 long-term potentiation and improved spatial and object recognition memory, notably at 12 months of age. Interestingly, these mice showed an increased expression of the phosphorylated transcription factor CREB, which may represent the main molecular correlate of the observed morphological and functional effects. Altogether, these findings indicate for the first time that F3/contactin plays a role in promoting adult hippocampal neurogenesis and that this effect correlates with improved synaptic function and memory.

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

“…Since the promoter element used in the TAG/F3 mice recapitulates a substantial part of normal CNTN2 expression, ectopic expression of CNTN1 is not limited to the cerebellum (Bizzoca et al, 2003;Bizzoca et al, 2012;Puzzo et al, 2013). In contrast to results from the cerebellum, in the early developing cerebral cortex, ectopic CNTN1 expression from the Cntn2 regulatory region -known to be expressed in cortical neural progenitors (see above) -was found…”

“…Ectopic expression of CNTN1 in development causes a similar suppression of neurogenesis to that seen in the cortex (Puzzo et al, 2013).…”

“…However, in the adult, where neurogenesis is known to continue (Kemperman et al, 2015) the opposite was seen, where neurogenesis was sharply increased as a consequence of the presence of the TAG/F3 transgene, resulting in increased hippocampal size and, in older mice, evidence of enhanced learning and memory, including elevated long term potentiation in CA1, increased pCREB levels (Lonze and Ginthy, 2013) and enhanced performance in spatial and object recognition tests (Puzzo et al, 2013).…”

Structural Characterization of the Extracellular Domain of CASPR2 and Insights into Its Association with the Novel Ligand Contactin1

“…CNTN1 is required for the cell surface localization of CASPR1 where they form a complex during the myelination process (9 -11). CNTN1 has also been implicated in hippocampal neurogenesis and cell proliferation as well as in synaptic plasticity and memory in the adult mouse (12). Expression of CNTN1 in both neurons and oligodendrocytes suggests a role in myelination, which has been confirmed by low levels of myelin basic protein in the CNTN1 KO mouse and by its interaction with other molecules involved in myelination (13)(14)(15)(16).…”

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

“…Moreover, contactin and its anchoring complex decrease in the CNS with age (34,76,77). Given that alterations in myelin and the resultant slowing of conduction are linked to impaired brain function (78,79), the up-regulation of contactin and syntrophin by vitamin D may reflect another mechanistic pathway by which vitamin D enhances cognitive function in aging (80). Fig.…”