Interplay between the dopaminergic system and the extracellular matrix in synaptics plasticity

Abstract

The most challenging task of our brain is to keep the balance between tenacity and plas-ticity. On the one hand, it is necessary that the brain networks possess a high degree of plasticity to be able to process new information. On the other hand, the brain needs the ability to stabilize structures for long-term information storage and memory formation. During development synapses and neuronal networks get stabilized over time which is paralleled by the maturation of the extracellular matrix (ECM). The brain’s ECM is formed by glia cells as well as neurons, enwraps and stabilizes synapses and is well-known as a key player in diverse plasticity processes, including learning and memory formation, as shown e.g. in mouse mutants lacking key ECM molecules. In turn, the activity status of a given neuronal network seems to induce remodeling of ECM struc-tures to allow plastic restructuring, but the molecular mechanisms underlying this re-modeling are largely unknown. The neuromodulator dopamine (DA) is a potent modula-tor of motivated learning processes, acting through five distinct but closely related G protein-coupled receptors (D1-D5). It was shown to enhance learning performance, e.g. in an auditory task in Mongolian gerbils when D1-like receptors were activated. Enzy-matic degradation of the ECM has also been shown to enhance learning performance of Mongolian gerbils in a frequency-modulated (FM) discrimination task and to restore juvenile-like structural plasticity. Moreover, stimulation of D1-like DA receptors was found to increase extracellular activity of the serine protease tPA (tissue-type plasmino-gen activator) being able to restructure the ECM. Therefore, I hypothesized that phar-macological stimulation of D1-like DA receptors will lead to an activation of ECM-modifying proteases, especially ADAMTS 4 and ADAMTS 5, and a restructuring of the ECM, thus contributing to synaptic plasticity. I investigated the most abundant chon-droitin sulfate proteoglycans (CSPGs) of the lectican family in the mature ECM- brevi-can (BC) and aggrecan (Acan). Indeed, I could show that systemic activation of D1-like DA receptors with the D1 receptor agonist SKF38393 results in enhanced BC and Acan cleavage in synaptosomal fractions of rat prefrontal cortex. To shed light on the underlying molecular mechanism, I performed in vitro experiments using rat dissociated cortical cultures at DIV21 when the ECM is considered to be ma-ture. I was able to confirm the obtained in vivo results. Furthermore, I could demon-strate that BC and Acan cleavage appears only at excitatory synapses. CSPGs of the lectican family, especially BC and Acan, are well known targets for enzymes of the ADAMTS family of proteases. Here, I could demonstrate in a knockdown approach that ADAMTS 4 as well as ADAMTS 5 are essential for DA-dependent cleavage of BC. Increased perisynaptic BC cleavage upon D1-like DA receptor activation is based on network activity and activity of postsynaptic sites, since sodium channels and NR2B-containing NMDARs are involved in the signalling. Furthermore, using optogenetic and pharmacological tools I could show that D1-like DA receptor-induced perisynaptic BC cleavage requires a co-signalling through PKA and CaMKII. Taken together, the results of this thesis contribute to a further understanding of poten-tial molecular mechanisms of synaptic ECM restructuring in DA-dependent processes. Furthermore, they provide a better understanding of DA-dependent remodeling of ma-ture ECM under physiological conditions due to activation of ADAMTS 4 and ADAMTS 5. Interestingly, molecules of the ECM as well as their cell surface receptors, cell adhesion molecules (CAMs) and ECM-modifying proteases are entangled in pro-cesses related to major brain diseases such as Alzheimer’s and Parkinson’s disease, or schizophrenia and epilepsy. Therefore, the here identified ECM-modifying proteases as well as proteolysis-derived ECM fragments and their appropriate cell surface receptors could serve as potential therapeutic targets to alleviate symptoms of e.g. neurodegenera-tive diseases.