Subcellular localization of intercellular adhesion molecule‐5 (telencephalin) in the visual cortex is not developmentally regulated in the absence of matrix metalloproteinase‐9

Abstract

The telencephalon-associated intercellular adhesion molecule 5 (Telencephalin; ICAM-5) regulates dendritic morphology in the developing brain. In vitro studies have shown that ICAM-5 is predominantly found within dendrites and immature dendritic protrusions, with reduced expression in mushroom spines, suggesting that ICAM-5 downregulation is critical for the maturation of synaptic structures. However, developmental expression of ICAM-5 has not been explored in depth at the ultrastructural level in intact brain tissue. To investigate the ultrastructural localization of ICAM-5 with transmission electron microscopy, we performed immunoperoxidase histochemistry for ICAM-5 in mouse visual cortex at postnatal day (P)14, a period of intense synaptogenesis, and at P28, when synapses mature. We observed the expected ICAM-5 expression in dendritic protrusions and shafts at both P14 and P28. ICAM-5 expression in these dendritic protrusions decreased in prevalence with developmental age to become predominantly localized to dendritic shafts by P28. To further understand the relationship between ICAM-5 and the endopeptidase metalloproteinase-9 (MMP-9), which mediates ICAM-5 cleavage following glutamate activation during postnatal development, we also explored ICAM-5 expression in MMP-9 null animals. This analysis revealed a similar expression of ICAM-5 in dendritic elements at P14 and P28; however an increased prevalence of ICAM-5 was noted in dendritic protrusions at P28 in the MMP-9 null animals, indicating that in the absence of MMP-9, there is no developmental shift in ICAM-5 subcellular localization. Our ultrastructural observations shed light on possible functions mediated by ICAM-5 and their regulation by extracellular proteases.

Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function

“…The pharmacological activation of NMDA receptors results in increased MMP-9-driven cleavage of the ICAM-5 extracellular domain (Tian et al, 2007; Ning et al, 2013). In MMP-9 null animals, ICAM-5 is not reduced at spines even after the age of maturation, supporting the idea that activity-driven cleavage diminishes filopodial ICAM-5 (Kelly et al, 2014). The extracellular domain cleavage of ICAM-5 may turn off the maturation-inhibiting signal in a number of ways.…”

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

“…Kelly et al . () analyzed the expression of the MMP‐9 substrate ICAM‐5 in the developing brain and reported a developmental shift in the subcellular localization of ICAM‐5. Notably, on postnatal day 28 (PND28) in MMP‐9‐null animals, this phenomenon did not occur.…”

“…Oliveira-Silva et al (2007) investigated the postnatal development of retinotectal projections and observed the highest MMP activity (presumably MMP-9) in the first postnatal week, with decreasing activity thereafter. Kelly et al (2014) analyzed the expression of the MMP-9 substrate ICAM-5 in the developing brain and reported a developmental shift in the subcellular localization of ICAM-5. Notably, on postnatal day 28 (PND28) in MMP-9-null animals, this phenomenon did not occur.…”

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

“…ICAM-5 downregulation is critical for the maturation of synaptic structures. Kelly et al 21 reported that ICAM-5 expression in dendritic protrusions in the mouse visual cortex decreased during this critical period to become predominantly localized to dendritic shafts. However, this phenomenon did not occur in MMP-9 knockout animals, indicating that no developmental shift in the subcellular localization of ICAM-5 occurs in the absence of MMP-9.…”