A deficiency of the link protein Bral2 affects the size of the extracellular space in the thalamus of aged mice

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The brain extracellular matrix (ECM) is composed predominantly of lecticans (chondroitin sulfate proteoglycans), tenascin, hyaluronan (HA), and link proteins (Asher, Scheibe, Keiser, & Bignami, 1995; Bekku et al., 2003). The link proteins have a crucial role in stabilizing the binding between lecticans and HA (Kwok, Carulli, & Fawcett, 2010), thus maintaining the condensed structure of ECM (Aspberg et al., 1997). Four link proteins have been described, three of which are expressed in the brain tissue: Crtl1/Hapln1 in the gray matter, Bral1/Hapln2 in the white matter, and Bral2/Hapln4 (Oohashi, Edamatsu, Bekku, & Carulli, 2015; Spicer, Joo, & Bowling, 2003). The last discovered link protein, Bral2, is typically coexpressed with Crtl1; however, Bral2 is expressed only in the distinct nuclei of the brainstem, cerebellum, and thalamus in the mature brain (Bekku et al., 2003). Recently, its specific role in adult brain development and function was assumed (Oohashi et al., 2015).
ECM plays various roles during development and in adulthood (Zimmermann & Dours‐Zimmermann, 2008), including the support of neural migration, proliferation, differentiation (Sobeih & Corfas, 2002), axon guidance, and synapse and memory formation (Dityatev & Schachner, 2003; Wright, Kramar, Meighan, & Harding, 2002). During development, ECM becomes focally condensed, creating ECM clusters around the nodes of Ranvier (Melendez‐Vasquez et al., 2005; Oohashi et al., 2002), perineuronal nets (PNNs) surrounding neuronal cell bodies and proximal dendrites (Wintergerst et al., 1996), and axonal coats (ACs) around axon terminals and synaptic boutons (Bruckner, Morawski, & Arendt, 2008; Gati et al., 2010). It seems that the formation of the ECM complexes and their condensation is important for fiber tract stabilization in the mature brain (Gundelfinger, Frischknecht, Choquet, & Heine, 2010; Zimmermann & Dours‐Zimmermann, 2008), for the termination of the critical period, and thus for decreased plasticity in adulthood (Galtrey & Fawcett, 2007), and plays a neuroprotective role (Morawski, Filippov, Tzinia, Tsilibary, & Vargova, 2014).
Once established, the structure of the adult‐type ECM is considered to be stable, with little or no change in its composition (Zimmermann & Dours‐Zimmermann, 2008). However, changes in the adult ECM may occur following a tissue injury (Kwok, Dick, Wang, & Fawcett, 2011). Moreover, reduced expression of chondroitin sulfate proteoglycans and fibronectin are part of the histological findings in aged rats, along with neuronal loss, astrogliosis, decreased number of synapses, and demyelination, and may contribute to the evolution of cognitive deficits during aging (Grady & Craik, 2000; Sykova et al., 2002).
ECM provides structural support maintaining the proper size and shape of the extracellular space (ECS). Moreover, negatively charged macromolecular chains of ECM proteoglycans may bind or repulse ions based on their charge, and create barriers affecting the diffusion of neuroactive substances such as ions, metabolites, hormones, or neurotransmitters (Sykova & Nicholson, 2008; Zimmermann & Dours‐Zimmermann, 2008). It has been shown previously that quantitative/qualitative alterations in the ECM composition affect the size and structure of the intercellular pores, with consequences on the concentration and diffusion of neuroactive substances in the ECS and, in turn, on CNS function (Sykova & Nicholson, 2008). For example, the disruption of ECM complexes around the nodes of Ranvier, observed in knockout mice deficient for link protein Bral1, was associated with a facilitated diffusion of small ions in the ECS and slower axonal conduction velocity (Bekku et al., 2010).
In this study, we have used the real‐time iontophoretic (RTI) method and diffusion‐weighted magnetic resonance imaging (DW‐MRI) to investigate the impact of Bral2 deletion and possible ECM remodeling on ECS diffusion parameters in the ventral posteromedial nucleus of the thalamus (VPM) in young adult and aged mice.
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