Conference Agenda

An abnormal activation of the immune system characterizes the pathogenesis of both psychiatric and neurological disorders and is known to influence neuronal network functioning in the cerebral cortex. However, little is known on how immune cells and soluble immune mediators influence the activity of subcortical structures, such as the basal ganglia (BG). The BG network exerts a key role in integrating cortical inputs and underlies motor learning as well as the regulation of behavior, emotional responses, and cognitive functions.This presentation will provide an overview on the neuro-immune cross-talk taking place in the BG network, with a specific focus on the modulation of synaptic properties in the nucleus striatum, the gateway to the BG. In this scenario, among the various soluble mediators, interleukin-17A (IL-17) is under the spotlight because of its emerging role as neuromodulator of synaptic transmission and plasticity in physiological and pathological conditions. Accordingly, recent data on the IL-17-dependent modulation of striatal synaptic plasticity will be presented, as a paradigmatic example on how neuroinflammatory processes might alter BG function and contribute to the pathogenesis of neuropsychiatric disorders.

Cognitive disfunction is a common trait often associated with early motor symptoms in Parkinson’s disease, whose neuropathological substrate is yet poorly understood. In this regard, clinical studies have reported the presence of inflammatory markers in the brain of parkinsonian patients with cognitive decline, pointing at neuroinflammation as a contributing pathological factor.

We investigated this issue in the translational rat model of PD based on the intranigral bilateral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc), which largely reproduces cardinal neuropathological and symptomatic features of the first stage of disease progression. H-αSynOs-infused rats displayed a mild cognitive decline three months after oligomer infusion, associated with altered electrophysiological activity in vivo in the anterior cingulate cortex (ACC), and a decreased expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4). The transcriptomic profiling of both the ACC and HC via RNA sequencing (RNA-seq) technology, revealed that gene involved in the innate and adaptive immune responses were mostly dysregulated in the ACC, while genes involved in mitochondrial homeostasis and generally in neuronal function were most affected in the HC. Accordingly, we observed astrogliosis and an increased number of inflammatory microglial cells expressing large amount of the cytokine TNF-α as compared to vehicle-infused rats, supporting a role of neuroinflammation in this symptomatic aspect. All together, we present a H-αSynO-induced rat model of PD that recapitulates cognitive symptoms of the disease, which adds to the classical motor aspects previously described. In this model we show an altered neuronal activity and dysregulated innate and adaptive immune responses of microglia and astroglia in distant cognitive-relevant regions, providing a neuropathological substrate for αSyn-induced cognitive deficits in PD.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, characterized by features that include misfolded protein aggregation, neuroinflammation, and cognitive deficits. Recent evidence indicates that among the cellular mechanisms implicated in PD, early glial activation and consequent neuroinflammation play a significant, though still poorly defined, role in the initiation of the pathological processes. Herein, we provide a demonstration that targeting a-syn and inflammation by non-pharmacological approach, such as motor exercise, represents a viable strategy to reduce disability and progression of motor symptoms in early PD. Clinical and preclinical studies have shown that exercise improves BDNF production and reduces inflammatory status.

Using a toxic model with intracerebral administration of human α-syn-pre-formed fibrils (PFF), we tested the hypothesis that intensive exercise prevents striatal synaptic alterations caused by α-syn overexpression and reduces neuroinflammation and α-syn spreading via the activation of BDNF-related pathways.

Our data show that corticostriatal long-term-potentiation (LTP), a form of plasticity lost in parkinsonian conditions, is restored in animals exposed to a physical training program. This effect is associated with a reduced spreading of α-syn in the substantia nigra pars compacta, indicating slower neurodegeneration in the active animals. In line with our hypothesis, the TrkB receptor’s blockade disrupted the exercise-induced LTP in the PFF active group, suggesting that an enhanced BDNF-TrkB pathway activity may underlie the rescue of synaptic plasticity. This exercise-induced BDNF plasticity depends on the activation of NMDA receptors bearing GluN2B subunits. These exercise-induced changes in neuronal functions resulted in beneficial effects on motor control and visuospatial cognition. Moreover, a decrease in microglia and astroglia reactivity was observed, with downregulation of neuroinflammatory processes.

Taken together, these findings demonstrate that intensive physical exercise exerts beneficial effects by rescuing early synaptic alterations induced by α-syn aggregates and that it has efficacy as a non-pharmacological therapy for PD.

Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation used to induce neuroplasticity in the brain and a non-pharmacological treatment in different neuropathological conditions. Although TMS has been shown to modulate several aspects of neuronal plasticity, there is still limited information on how TMS works at the cellular and molecular levels, as well as its impact on non-neuronal cells, like astrocytes and microglia and other different components of the Blood-Brain-Barrier (BBB), the pericytes and the endothelial cells (EC).

This study investigated changes in RNA and protein levels of the main components of the BBB following different treatments of theta-burst stimulation (TBS), repetitive TMS patterns, such as continuous (cTBS) and intermittent (iTBS) protocols, used in a 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rat model.

In the striatum of parkinsonian animals, mRNA and protein levels of markers of pericytes, such as PDGFβ, decreased significantly after the lesion compared to control animals. Notably, in 6-OHDA-lesioned animals, the decrease of pericytes markers correlated with a reduction of PECAM-1 (also known as CD31), a marker of vessel endothelial cells, and these changes were associated with impairments in brain microvasculature. After the injury, treatment with iTBS protected both pericytes and endothelial cells of the striatal microvasculature from 6-OHDA-induced damage. Similarly, cTBS treatment restores microvessels integrity by restoring lectin and PECAM-1 expression, thus improving microvasculature integrity, that was found similar to what was observed in unlesioned animals.

Collectively, these findings demonstrate the ability of TMS to modulate specific aspects of non-neuronal cell phenotype and restore the microvasculature integrity, highly impaired after 6-OHDA lesion, potentially contributing to the known effects of TMS on neuroprotection.