Role of PI3K isoforms in linking synaptic plasticity and metabolism in neurons and astrocytes

Laburpena

Synaptic plasticity is based on the ability of the brain to undergo activity-dependent modifications in response to experience. This property has been extensively studied, but the underlying molecular mechanisms are still not fully understood. Moreover, the connection between synaptic activity and metabolism is gaining importance in the field and the role of astrocytes in this aspect is crucial. Class IA phosphatidylinositol 3-kinases (PI3Ks) are heterodimers composed of a p110 catalytic subunit, of which there are three isoforms (p110α, p110β and p110δ), and a p85 regulatory subunit. These kinases are involved in several processes including synaptic plasticity, but their specific role in astrocytes and in neuronal metabolism is still unknown. We have addressed this issue using a genetic approach. Given the embryonic lethality of the genetic knockouts (KOs) for two of the catalytic isoforms, p110α and p110β, we used adult floxed mice and created a conditional, spatially-restricted, cell type-specific KO of each isoform by injecting an adenoassociated virus expressing the Cre recombinase under the neuronal or astrocytic-specific promoter, CamKII and GFAP respectively, in the hippocampus. In this way, we had four conditional KO models (p110α or p110β neuronal KO or astrocytic KO) to assess the differential roles of each isoform in these two brain cell types regarding synaptic plasticity and metabolism. For the neuronal KOs, our results demonstrate that the lack of p110α produces a downregulation of glycolysis and an upregulation of oxidative phosphorylation and mitochondrial function, increasing both their size and activity. On the other hand, the ablation of p110β upregulates glycolysis and ATP production, even though the size of mitochondria is slightly smaller. These metabolic adaptations may be impacting on the synaptic plasticity alterations described in previous studies from our group. In the case of the astrocytic KOs, p110α is required for LTP and p110β for LTD, both having an impact on memory processes. We have linked the LTP impairment in the p110α astrocytic KO to a D-serine deficiency, that can be rescued in vitro with the addition of both D-serine and its precursor, L-serine. Finally, we were able to ameliorate the behavioral impairment previously observed with an L-serine in vivo treatment. On the other hand, the LTD impairment in the p110β astrocytic KO was linked to a deficient astrocyte-to-neuron glutamate-mediated communication. The results in this PhD thesis show the functional diversity between p110α and p110β in two different cell types in the brain and link for the first time the function of PI3K to cerebral metabolism and its influence in synaptic plasticity.