Role of Class IA PI3K isoforms in synaptic plasticity and cognitive function

Resumen

Learning and memory are cognitive functions based on the ability of the brain to modify the existing neuronal connections by strengthening or weakening them in response to individual experience. This property is known as synaptic plasticity and albeit being extensively studied for the past decades, the underlying molecular mechanisms are still not fully understood. Class IA phosphatidylinositol 3-kinases (PI3Ks) have been shown to be required for two opposing forms of synaptic plasticity, namely long-term potentiation and depression (LTP and LTD, respectively). They are heterodimers composed of a catalytic subunit of which there are three isoforms (p110α, p110β and p110δ) and a regulatory subunit (p85). There is emerging evidence regarding the differential regulation of the catalytic subunit isoforms, which could explain the functional diversity of PI3Ks regarding their requirement for synaptic plasticity. However, the use of non-selective PI3K inhibitors and the embryonic lethality of the genetic knockouts thus far has hindered the identification of specific physiological functions of these isoforms. Here, we used adult floxed mice coupled to neuron-specific Cre expression for specifically removing either the gene corresponding to p110α or p110β (PIK3CA and PIK3CB, respectively) and to assess the differential roles of each isoform in synaptic plasticity and cognitive function. As a complementary approach, we have also used isoform-specific inhibitors and shRNA technology. Our results demonstrate that both isoforms play a role in LTP expression but only p110β is required for LTD. In addition, neuronal ablation of p110α or p110β has differential consequences on short-term synaptic plasticity and basal synaptic transmission. We have shown that p110α is required to a greater extent than p110β for neuronal architecture and is the only one required for dendritic spine maintenance. Moreover, we have found that neuronal-specific deletion of p110α or p110β in the hippocampus of floxed mice causes alterations in learning/memory and sociability. Lastly, we have identified that the functions of both isoforms are spatially segregated and the lack of each subunit has consequences on different signaling pathways. The results in this PhD thesis show that there is functional diversity between p110α and p110β. In this manner, this work contributes to the understanding of the signaling cascades that elicit the different paradigms of synaptic plasticity as well as the consequences of impaired synaptic function in the hippocampus on cognitive function