The term plasticity refers to the ability of the nervous system to dynamically adjust its structure and function following specific stimuli. Our laboratory has been studying for a long time the mechanisms by which the visual system reacts to changes in environmental influences (e.g., to alterations in visual input), especially during “critical periods” early in development (Restani et al., Neuron 2009; Deidda et al., Nat Neurosci, 2015). Plasticity is also crucial in the recovery from brain damage – for example, via the formation of novel synaptic contacts that vicariate those lost as a consequence of injury and disease (Spalletti et al., eLife 2017; Terrigno et al., Stem Cell Rep 2018). However, plasticity can also be maladaptive, e.g. in the case of the epileptogenic processes that follow a brain insult. In such cases, circuit reorganization lead to a persistent network hyperexcitability and propensity for spontaneous seizures (Cerri et al., J Neurosci 2016). In the laboratory, we study processes of neural plasticity occurring in pathological disorders of the central nervous system. A better understanding of these plastic processes may be employed for devising more effective therapeutic options for these pathologies.
Stroke is one of the leading causes of long-term disability, and there is an obvious need for appropriate animal models to guide the development of more effective rehabilitation therapies after stroke. We concentrate on studies of rehabilitation and plasticity following ischemic lesions to forelimb motor cortical areas in the mouse. Recently, we have shown that a combined protocol of robotic rehabilitation and transient silencing of the contralesional hemisphere restores pre-stroke motor patterns in mice (Spalletti et al., eLife 2017). Second, we have shown that cortical progenitors transplanted in the peri-infarct zone extend axonal projections and stimulate functional restoration after photothrombotic ischemia (Terrigno et al., 2018).
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Gliomas are usually fatal and largely unresponsive to all available treatments. We have studied the antineoplastic effects of the bacterial enzyme CNF1 (cytotoxic necrotizing factor-1) in a mouse model of glioma. CNF1 causes a long-lasting activation of Rho GTPases and displays a double action: (i) it leads to actin stabilization, blockade of cytodieresis, multinucleation and eventually cell death in proliferating glioma cells; (ii) it promotes neuron health and plasticity, with an increase in dendritic and spine growth. We have shown that CNF1 is effective in halting growth of the tumoral mass and at the same time preserving the functionality of the neurons surrounding the glioma (Vannini et al., Neuro-Oncol 2016). Currently, we are exploring how growth of the tumor reverberates on the physiological properties of peritumoral neurons, and how the altered synaptic activity may influence tumor proliferation.
Epilepsy is one the most common neurological disorders and is characterized by spontaneous recurrent seizures. We are studying the cellular bases of network hyperexcitability in two murine models of epilepsy: a model of neocortical epilepsy triggered by tetanus neurotoxin (Mainardi et al., Epilepsia 2012; Vannini et al., BSAF 2016), and a model of temporal lobe epilepsy induced by intrahippocampal kainic acid (Antonucci et al., Epilepsia 2009). We have recently shown that systemic inflammatory factors enhance seizure susceptibility within the epileptic focus via the chemokine CCL2 (Cerri et al., J Neurosci 2016).
Botulinum neurotoxins (BoNTs) are metalloproteases capable of blocking the synaptic vesicle release machinery by cleaving SNARE proteins. BoNT/A, in particular, is able to induce a sustained yet transitory blockade of acetylcholine release from peripheral nerve terminals. Owing to these characteristics, it has been beneficially employed in the clinical practice to reduce muscle hyperactivity (such as in spasticity and dystonia) with long-lasting therapeutic effects. However, not all BoNT/A effects can be explained by an action at peripheral nerve terminals. Over the last years, we have shown that BoNT/A can be retrogradely transported from the periphery to directly affect the central nervous system (Fig. 2). This knowledge is important for a complete understanding of the mechanisms of action of BoNT/A, an issue that is highly relevant in the context of the expanding clinical applications of this toxin.
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