The role of PTEN in synaptic and cognitive function and in social behavior

Resumen

The establishment of functional brain circuits depends on the correct formation of synaptic connections among neurons, followed by an intense activity-dependent remodeling during postnatal development and adulthood. This process, known as synaptic plasticity, is highly regulated by phosphatidilinositol-3 kinase (PI3K) pathway, which also regulates cell growth, proliferation and cell survival. PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a negative regulator of this pathway and is highly expressed in brain, where it controls synaptogenesis and synaptic plasticity. PTEN activity is required for NMDA receptor-dependent long-term depression (LTD), and its anchoring to the postsynaptic terminal requires the C-terminal PDZ binding motif of PTEN. PTEN has been linked to Autism Spectrum Disorders (ASD), since mutations in this gene are associated with a form of autism that is accompanied by macrocephaly (PTEN-ASD). These patients show poorly developed communication skills, altered social behavior, stereotypic movements and higher anxiety. The neuronal control of these complex behaviors is still being elucidated, and appears to involve multiple brain regions, such as the amygdala and the hippocampus. Thus, in this work I have evaluated the role of PTEN in these brain areas and its implication in synaptic plasticity, cognitive processes and social behavior. To explore the importance of PTEN for synaptic organization and cognitive function, I have employed two transgenic mice. Ptentg, presenting moderate overexpression of PTEN, and PTEN-PDZ, in which PTEN lacks the last four amino acids, therefore removing the PDZ binding motif. I found that Ptentg mice present microcephaly, with reduced hippocampal volume and neuron number. These parameters are normal in the lateral amygdala (LA), although LA neurons display reduced dendritic complexity and spine density. Ultrastructure analysis revealed decreased synapse density in both brain regions and reduced PSD length in the LA. Conversely, PTEN-DPDZ mice present macrocephaly, similar to the phenotype found in patients with PTEN-ASD, suggesting a bidirectional modulation of brain anatomy by PTEN in a region- and PDZ-dependent manner. These anatomical changes were correlated with alterations in synaptic function using electrophysiological recordings. Thus Ptentg mice present depressed excitatory basal synaptic transmission in the hippocampus and in the thalamic input to the LA, impaired long-term potentiation (LTP) in the hippocampus and in the cortical input to the LA and enhanced long-term depression (LTD) in the cortical input to the LA. On the other hand, PTEN-DPDZ mice present normal basal synaptic transmission and deficient LTD in the hippocampus and the cortical input to the LA. These findings revealed an input-specific modulation of synaptic plasticity by PTEN and its implication in hippocampal and cortico-LA pathway LTD in a PDZ-dependent manner. To further study whether these synaptic alterations have an impact on behavior, I carried out several tests related to hippocampal and LA function, as well as those behaviors related to ASD. Ptentg mice present impaired spatial and fear memory, which could be related to alterations in LTP in the hippocampus and the LA, respectively. With respect to ASD related behaviors, impaired communication skills, normal stereotyped behavior, decreased anxiety and prosocial behavior were found in Ptentg mice. Conversely, PTEN-DPDZ mice present normal communication skills, normal anxiety-like behavior and impaired social behavior. Thus, PTEN is involved in the modulation of several behaviors, but only social behavior seems to require PTEN PDZ interactions. These findings suggest a relationship between a specific form of synaptic plasticity in the cortical input to the LA and social behaviour under PTEN regulation.