B. Di Benedetto

Pink1-deficiency in mice impairs gait, olfaction and serotonergic innervation of the olfactory bulb

Parkinsons Disease (PD) is the most common neurodegenerative movement disorder. Autosomal-recessive mutations in the mitochondrial protein kinase PINK1 (PTEN-induced kinase 1) account for 1-2% of the hereditary early-onset cases. To study the mechanisms underlying disease development, we generated Pink1-deficient mice. In analogy to other genetic loss-of-function mouse models, Pink1(-/-) mice did not show morphological alterations in the dopaminergic system. As a consequence, no gross motor dysfunctions were observed indicating that these mice do not develop the cardinal symptoms of PD. Nonetheless, symptoms which develop mainly before bradykinesia, rigidity and resting tremor were clearly evident in Pink1-deficient mice. These symptoms were gait alterations and olfactory dysfunctions. Remarkably in the glomerular layer of the olfactory bulb the density of serotonergic fibers was significantly reduced. Concerning mitochondrial morphology, neurons in Pink1(-/-) mice had less fragmented mitochondria. In contrast, upon acute knock-down of Pink1 increased mitochondrial fragmentation was observed in neuronal cultures. This fragmentation was, however, evened out within days. Taken together, we demonstrate that Pink1-deficient mice exhibit behavioral symptoms of early phases of PD and present systematic experimental evidence for compensation of Pink1-deficiency at the cellular level. Thus, Pink1-deficient mice represent a model for the early phases of PD in which compensation may still impede the onset of neurodegeneration. Consequently, these mice are a valuable tool for studying Pink1-related PD development, as well as for searching for reliable PD biomarkers.

Targeting Glia Cells: Novel Perspectives for the Treatment of Neuropsychiatric Diseases

Neuropsychiatric disorders are devastating mental illnesses with a high economic burden. The additional morbidity associated with social issues that arises along with the course of these diseases increases the need for a clear understanding of their etiopathogenesis to allow an implementation of novel pharmacological strategies. Yet a poor knowledge about interactions occurring at the glia-neuron interface in health and disease still hampers innovative discoveries, despite the fact that glia cells have been long described to actively participate in the regulation of brain circuits. The purpose of this review was to collect the scattered literature on the involvement of glia cells in neuropsychiatric disorders and to describe how also these cells besides neurons might be responsive to current pharmacological interventions. We hope thereby to offer alternative approaches for investigations that may open avenues to search for new potential targets for drug discovery.

Acute antidepressant treatment differently modulates ERK/MAPK activation in neurons and astrocytes of the adult mouse prefrontal cortex

The onset of action of antidepressants (ADs) usually takes several weeks, but first molecular responses to these drugs may appear already after acute administration. The Extracellular Signal-regulated Kinase/Mitogen-Activated Protein Kinase (ERK/MAPK) signaling pathway is a target of ADs and an important pathway involved in cellular plasticity. In major depressive disorder (MDD), especially the prefrontal cortex (PFC) and hippocampus (Hip) are most likely affected in depressive patients and recent work revealed a hyperactivated ERK signaling in the rat PFC after chronic stress, a precipitating factor for MDD. Strong evidences support that not only neurons but also astrocytes participate in neuronal activity and may therefore additionally be a substrate of AD action. In this study, we show by Western blot that neither fluoxetine (FLX) nor desipramine (DMI) preferentially affects the activation of one of the two ERK isoforms, ERK1 and ERK2, with respect to the other. Further immunohistochemical analysis in the PFC revealed that basal levels of phospho-activated ERK (pERK) are mostly found in neurons in contrast to very few astrocytes. Both ADs can inhibit neuronal pERK as early as 15 min after drug administration with peculiar regional and layer specificities. Contrarily, at this time point none of the two ADs shows a clear modulation of astrocytic pERK. We propose that this mechanism of action of ADs may be protective against an exacerbated cortical ERK activity that may exert detrimental effects on susceptible neuronal populations. Our findings on acute effects of AD treatment in the adult mouse PFC encourage to examine further how this treatment might influence pERK in animal models of depression to identify early targets of AD action.

Lack of interaction of endocannabinoids and 5-HT3 neurotransmission in associative fear circuits of the amygdala: Evidence from electrophysiological and behavioural experiments

Both the serotonergic and the endocannabinoid system play a major role in mediating fear and anxiety. In the basolateral amygdala (BLA) it has been shown that the cannabinoid receptor 1 (CB1) is highly co-expressed with 5-HT3 receptors on GABAergic interneurons suggesting that 5-HT3 receptor activity modulates CB1-mediated effects on inhibitory synaptic transmission. In the present study, we investigated the possible interactions of CB1 and 5-HT3-mediated neuronal processes in the BLA using electrophysiological and behavioural approaches. Whole-cell patch-clamp recordings were performed in coronal brain slices of mice. Electric stimuli were delivered to the lateral amygdala to evoke GABAA receptor-mediated inhibitory postsynaptic currents (GABAA-eIPSCs) in the BLA. The induction of LTDi, a CB1-mediated depression of inhibitory synaptic transmission, was neither affected by the 5-HT3 antagonists ondansetron (OND; 20 µM) and tropisetron (Trop; 50 nM) nor by the 5-HT3 agonists SR57227A (10 µM). In auditory fear conditioning tests, mice treated with SR57227A (3.0mg/kg i.p.) showed sustained freezing, whereas treatment with Trop (1.0 mg/kg i.p.) decreased the expression of conditioned fear. These effects were overruled by the CB1 antagonist rimonabant (RIM; 3.0 mg/kg), which caused increased freezing with or without co-treatment with Trop. In summary, these experiments do not support a functional interaction between CB1 and 5-HT3 receptors at the level of GABA neurotransmission in the BLA nor in terms of fear regulation.