Abstract
Synapse formation and function are critical events for the brain function and cognition. Astrocytes are active participants in the control of synapses during development and adulthood, but the mechanisms underlying astrocyte synaptogenic potential only began to be better understood recently. Currently, new drugs and molecules, including the flavonoids, have been studied as therapeutic alternatives for modulation of cognitive processes in physiological and pathological conditions. However, the cellular targets and mechanisms of actions of flavonoids remain poorly elucidated. In the present study, we investigated the effects of hesperidin on memory and its cellular and molecular targets in vivo and in vitro, by using a short-term protocol of treatment. The novel object recognition test (NOR) was used to evaluate memory performance of mice intraperitoneally treated with hesperidin 30 min before the training and again before the test phase. The direct effects of hesperidin on synapses and astrocytes were also investigated using in vitro approaches. Here, we described hesperidin as a new drug able to improve memory in healthy adult mice by two main mechanisms: directly, by inducing synapse formation and function between hippocampal and cortical neurons; and indirectly, by enhancing the synaptogenic ability of cortical astrocytes mainly due to increased secretion of transforming growth factor beta-1 (TGF-β1) by these cells. Our data reinforces the known neuroprotective effect of hesperidin and, by the first time, characterizes its synaptogenic action on the central nervous system (CNS), pointing astrocytes and TGF-β1 signaling as new cellular and molecular targets of hesperidin. Our work provides not only new data regarding flavonoid’s actions on the CNS but also shed light on possible new therapeutic alternative based on astrocyte biology.
Highlights
Synapse formation and plasticity are key properties throughout the life of animals and are crucial to their cognitive abilities, such as learning and memory
Effect of Astrocyte-Conditioned Medium (ACM)-Hesperidin was strongly reduced by addition of αTGF-β1 (Figures 4D–F). These results suggest that hesperidin improves the synaptogenic potential of astrocytes and points to transforming growth factor beta-1 (TGF-β1) as an important synaptogenic factor secreted by astrocytes in response to hesperidin
We observed a 30% increase of phospho-SMADs 2/3 levels in the hippocampus of mice injected with hesperidin (Figure 5F). These results indicate that the TGF-β1 signaling is modulated by hesperidin in vitro and in vivo and TGF-β1 is one of the indentified molecules that mediates the synaptogenic action of hesperidin-treated astrocytes
Summary
Synapse formation and plasticity are key properties throughout the life of animals and are crucial to their cognitive abilities, such as learning and memory. Cellular and molecular mechanisms underlying the astrocytic control of synapses in health and disease are only beginning to be better understood. Astrocytes closely and dynamically control synapses by two known mechanisms: expression of adhesion molecules (Hama et al, 2004) and secretion of soluble factors, such as cholesterol (Mauch et al, 2001), thrombospondin 1 (Christopherson et al, 2005), hevin (Kucukdereli et al, 2011), glypicans (Allen et al, 2012) and transforming growth factor beta-1 (TGF-β1; Diniz et al, 2012). Elegant studies have pointed to the critical role of some of these molecules secreted by adult murine and human astrocytes in the formation of functional synapses (Han et al, 2013; Zhang et al, 2016). The secretion profile of astrocytes has been investigated recently (Orre et al, 2014; Zhang et al, 2016), the mechanisms involved in the control of astrocyte secretion are still poorly known
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