Our studies demonstrate that attenuation of the neural ECM, particularly in the form of hyaluronic acid and chondroitin sulfate-rich perineuronal nets, is found in the ketamine model of schizophrenia (Matuszko et al., 2017) and may result in epileptiform activity (Garau et al., 2015). The mechanisms underlying ECM attenuation involve an upregulation of the activities of matrix metalloproteinases, such as ADAMTS4/5 and MMP-9. They appeared to be under the control of dopaminergic and serotoninergic systems, involving D1-like and 5-HT7 receptors, respectively (Mitlöhner et al., 2017; Bijata et al., 2017).
Our pioneering works revealed the role of ECM in synaptic plasticity (Saghatelyan et al., 2000; 2001; Bukalo et al., 2001). For example, tenascin-C supports induction of long-term potentiation (LTP) at CA3-CA1 synapses and the extinction of fear memories by regulation of L-type voltage-gated Ca2+ channels (Evers et al., 2002; Morellini et al., 2017). Similarly, hyaluronic acid regulates synaptic plasticity through these channels (Kochlamazashvili et al., 2010). Another mechanism involves a control of axonal excitability by heparan sulfates. In vivo, heparinase treatment impairs context discrimination in a fear conditioning paradigm and oscillatory network activity in the low theta frequency band (Minge et al., 2017).
In aged brains and dementia, ECM expression is elevated. Hence, our ongoing research is focused on analysis of how ECM upregulation effects synaptic plasticity and cell excitability.
The mechanistic studies of ECM-mediated regulations are complemented in our group by search of the most potent and safe compounds that could be brought into clinical trials to target the neural ECM in neurodegenerative diseases. The effects of promising leads are tested in animal models of AD, FTD, tauopathies and depression, as well as in neuron-astrocyte co-cultures derived from patient iPSCs.
For the preclinical characterization of ECM targeting drugs, we are employing the established battery of synaptic and cognitive assays. Furthermore, we are developing new assays to study the role of ECM in the regulation of neural network activity, particularly during reversal learning. To monitor the functional dynamics of neural networks, as well as the structure of microglia and tetrapartite synapses, we use multielectrode recordings (Senkov et al., 2016) and two-photon imaging of Ca2+ indicator (GCaMP6)-expressing neurons or microglia (fluorescently labelled in CX3CR1::GFP mice) as well as customized AAV-based fluorescent probes for the labeling of ECM, pre- and postsynapses. Live imaging is performed in the retrosplenial cortex of anaesthetized or awake animals placed in virtual reality.
As there are major benefits of stimulating synaptogenesis in models of AD, we aim to promote synaptogenesis using synthetic ECM-like molecules or by targeting endogenous extracellular proteinases.