Mammalian hippocampal neuronal plasticity under normal and pathological conditions

Neuroplasticity is a term that includes all the functional and structural changes within a neural circuit in response to external or internal events, changes at synaptic level, in the morphology, or in the number of cells. These changes are related with functional modifications and have great relevance under physiological conditions and in neuropathology. The malleability of the nervous system has a central role in shaping the brain during prenatal and early postnatal development, in the childhood, but also in the adulthood, supporting vital functions, such as learning and memory. Therefore, the first part of this PhD thesis is focused on study about the mechanism of physiological plasticity in the hippocampus in relation with network activation induced by common every-day experiences, such as physical activity. Hippocampus, indeed, attracts great attention in the neuroscience research field because it takes part to certain types of learning and memory but also because of its extraordinary degree of neuronal plasticity. In this structure, much of the attention is mainly focused on neuronal plasticity phenomena, such as synaptic Long Term Potentiation (LTP) and adult neurogenesis: this last phenomenon represents a fascinating example of plasticity occurring in a specific hippocampal area called Dentate Gyrus (DG). Here, new granule cells are daily generated and incorporated in the existing network. In the hippocampus, stem/progenitor cell proliferation and newly-generated granule cell integration are affected by numerous stimulus both physiological and pathological. In keeping with this statement, physical exercise represents a pro-neurogenic activity. Our previous findings highlighted that a brief physical activity, and in particular voluntary running, produces short-term effects in very immature newborn granule cells of adult DG. Here, the attention is shifted in the research for possible long-lasting effects of voluntary running on newly-generated granule cells, evaluating morphological and possible functional implications related with this activity, with the purpose of removing part of the shadows upon the possible mechanism of cognitive enhancement widely reported in association with physical exercise. Additionally, since abnormal plastic adaptation underlies many neural diseases, the second part of this thesis has considered two pathologies, depression and epilepsy, in order to uncover and highlight possible treatments able to influence, or prevent, the aberrant plastic support to these neuropathologies. Concerning depression, the focus was placed on the study of Fibroblast Growth Factor Receptor 1 – 5-hydroxytryptamine 1A (FGFR1-5HT1A) heteroreceptor complex role in depression, which is a receptor-receptor (R-R) interaction of extreme interest since it represents the meeting point between two theories of depression, the serotoninergic and the neurotrophic factor hypotheses. The FGFR1-5HT1A heteroreceptor complex is reported to exist in hippocampus. In addition, combined agonist treatment influences cellular throphism and morphology, suggesting that activation of FGFR1-5HT1A heteroreceptor complex might be related with antidepressant effect of serotonin in the brain and, combined activation of both receptors might result in more rapid and stronger antidepressant action than that found with Selective Serotonin Reuptake Inhibitors (SSRIs). Indeed, an important clinical pursuit in the depression field is the research for fast-acting treatments or molecules able to speed up the effects of the canonical anti-depressive drugs, since commonly available treatments exert their therapeutic action after a delay that last from weeks to months. Thus, the attention has been focused on a first evaluation about the therapeutic potential of combined FGFR1 and 5HT1A agonist treatment, which has been firstly tested on Sprague Dawley (SD) rats, using electrophysiological, molecular and behavioural approaches. Afterward, to evaluate if disturbances of the FGFR1-5HT1A heteroreceptor complex might exist in depression and if the combined treatment with the agonists of the FRGR1 and 5-HT1A could exert antidepressant effects, the attention was moved on Flinders Sensitive Line Rats (FSL), a well-known model of depression. Actually, the potential existence of disturbances in depression at FGFR1-5HT1A heteroreceptor complex level could represent an exciting finding since it might confirm these complexes as valid targets for future therapeutic treatments with possible fast-acting properties. The other pathology investigated in the second part of this PhD thesis is the mesial temporal lobe epilepsy (MTLE), the most common form of localization-related epilepsy, which is characterised by progressive plastic rearrangements that lead to the chronicization of the disease and the aberrant remodelling of the hippocampal network. Treatment able to counteract the chronicization of epilepsy represents an unmet clinical need. Previous findings from our laboratory of physiology suggested a potential and promising role of Vitamin E (as -tocopherol) as antiepileptogenic treatment, which might act through different mechanisms than anti-oxidant one. To validate this assumption, using the kainate rat model of epilepsy, the excitability of hippocampus circuitry, the neuroinflammation markers, neuron cell death and microRNA (miRNAs) expression, have been investigated in adult rat after 15-days of -tocopherol treatment. Overall, essential cognitive process but also several neuropathologies have a common underlying feature called brain plasticity, which plays a double but opposite role in these different conditions, thus being of huge interest for neuroscience and all human life. Accordingly, managing to manipulate brain plasticity is gaining great attraction for its potential in health and disease. On one hand, it might improve essential features as learning, memory and cognition: indeed, a brief physical activity creates short-term and long-lasting modifications in hippocampus, which could influence future network activity and lead to cognitive enhancement. On the other hand, the research for treatments potentially able to counteract aberrant plastic changes in disease, as those observed in depression or epilepsy, might represent a promising approach aimed to correct the mechanisms behind the pathology and not the symptoms themselves.