The Extracellular Matrix Molecule Hyaluronic Acid Regulates Hippocampal Synaptic Plasticity by Modulating Postsynaptic L-Type Ca2+ Channels

Abstract

Although the extracellular matrix plays an important role in regulating use-dependent synaptic plasticity, the underlying molecular mechanisms are poorly understood. Here we examined the synaptic function of hyaluronic acid (HA), a major component of the extracellular matrix. Enzymatic removal of HA with hyaluronidase reduced nifedipine-sensitive whole-cell Ca(2+) currents, decreased Ca(2+) transients mediated by L-type voltage-dependent Ca(2+) channels (L-VDCCs) in postsynaptic dendritic shafts and spines, and abolished an L-VDCC-dependent component of long-term potentiation (LTP) at the CA3-CA1 synapses in the hippocampus. Adding exogenous HA, either by bath perfusion or via local delivery near recorded synapses, completely rescued this LTP component. In a heterologous expression system, exogenous HA rapidly increased currents mediated by Ca(v)1.2, but not Ca(v)1.3, subunit-containing L-VDCCs, whereas intrahippocampal injection of hyaluronidase impaired contextual fear conditioning. Our observations unveil a previously unrecognized mechanism by which the perisynaptic extracellular matrix influences use-dependent synaptic plasticity through regulation of dendritic Ca(2+) channels.

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

“…Recently, we demonstrated in vitro that a decrease of the perisynaptic ECM also modulates synapses at the functional level by enhancing lateral diffusion of glutamate receptors on the neuronal surface, which impacts synaptic short-term plasticity (10). Lack of several ECM proteins such as tenascin-R or brevican or chondroitin sulfates results in increased excitability of perisomatic interneurons, GABA A -dependent inhibition of longterm potentiation (LTP) induction (11,26), impaired maintenance of LTP (27,28), or impaired L-type voltage-dependent CA 2+ -channel (L-VDCC; Cav1.2)-dependent LTP induction (9). Thus, taken together, the ECM influences short-and longterm plasticity of synapses and thereby potentially regulates signal processing within a neuronal network during learning.…”

“…Enzymatic degradation of the ECM in adult animals has been demonstrated to restore such forms of developmental (juvenile) plasticity with respect to topographical map plasticity in the visual cortex (4), fearresponse-mediating circuits in the amygdala (5), spinal cord injuries (6,7), and song learning circuits of zebra finches (8). In addition, enzymatic ECM removal altered several forms of synaptic plasticity in vitro and in vivo (9)(10)(11)(12). However, even though structural stability of networks acquired during developmental phases is essential for neuronal efficiency, mechanisms allowing synaptic remodeling are key events during learning and memory formation throughout life (13).…”

“…We recently demonstrated that endogenous proteases moderately digesting specific components of the ECM are regulated in an activity-dependent manner (2,14) and ECM removal modulates synaptic short-term plasticity by synaptic exchange of postsynaptic glutamate receptors (10,15). Further, ECM modulation enhances synaptic short-term plasticity by affecting voltage-dependent calcium channels (9). These findings challenge the view of the purely stabilizing role of ECM in the brain and indicate a potential regulatory switch for plastic network adaptations within the adult brain at the level of individual synapses by modulating the extracellular space (16).…”

Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus

“…The most important of the latter is α-CaMKII (33)(34)(35)(36). An important source of [Ca 2+ ] i are the long-acting voltage-dependent calcium channels (L-VDCCs), which have been proposed to play some role in memory processes (37)(38)(39)(40). CaMKII has many purported or demonstrated roles in consolidation and perhaps in maintenance (10); one that has been recently suggested is to serve as a scaffold for proteasomes to act on dendritic spines (41).…”

BODIPY-Conjugated Xyloside Primes Fluorescent Glycosaminoglycans in the Inner Ear of Opsanus tau

“…In this case, disruption of GAG synthesis or remodeling could alter hair bundle movement and mechanoelectrical transduction (MET) currents. There is also evidence that GAGs play an important role at synapses and, when altered, can result in impaired short-term plasticity and transmission (Albiñana et al, 2015;Kochlamazashvili et al, 2010;Chicoine et al, 2004;Frischknecht et al, 2009). Here, we describe a new fluorescently conjugated xyloside, BODIPY-xyloside (BX), developed to study the turnover and impact of primed GAGs in the physiology of the inner ear vestibular organs.…”