PTEN: a new player controlling structural and functional synaptic plasticity

Abstract

Phosphoinositide 3-kinase (PI 3-kinase) is a ubiquitous enzyme that catalyses the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3). PI 3-kinase driven generation of PIP3 activates various downstream signalling cascades which in turn regulate numerous biological processes including growth, metabolism, proliferation, migration and cell size. PTEN (phosphatase and tensin homologue deleted on chromosome 10), which was originally identified as a tumour promoter, is a constitutively active lipid phosphatase that opposes PI 3-kinase-dependent signalling by promoting dephosphorylation of PIP3 into PIP2. PTEN is highly expressed in neurons and several lines of evidence support a role for PTEN in regulating important neuronal functions. Indeed, familial mutations that result in PTEN inactivation have been linked to neurological disorders such as ataxia, mental retardation and seizures (Backman et al. 2001). Moreover, loss of PTEN function at early stages of development results in widespread deficits in neuronal growth, synaptogenesis and synaptic plasticity suggesting additional roles for PTEN in these processes. However, it is not clear if PTEN-linked synaptic impairments are a direct consequence of loss of PTEN function or are secondary to PTEN-driven alterations in neuronal morphology. A recent insightful study by Sperow et al. (2012) in The Journal of Physiology aims to address this issue. This study demonstrates that the structural and functional properties of hippocampal synapses are independently controlled by PTEN and that PTEN plays a direct role in activity-dependent hippocampal synaptic plasticity. Several studies have observed that a key feature of deleting PTEN during CNS development is progressive hypertrophy of neuronal dendrites and spines as well as a marked increase in the size of neurons and synapses. PTEN deletion or down-regulation in hippocampal neurons also results in impairments in two forms of activity-dependent synaptic plasticity, namely long-term potentiation (LTP) and long-term depression (LTD). In order to determine if the structural and functional effects of PTEN on hippocampal synapses are related, Sperow and colleagues generated transgenic mice with conditional knockout of PTEN in forebrain excitatory neurons. As PTEN deletion was apparent after postnatal day 14 (P14) in these mice, the impact of PTEN deletion on hippocampal synaptic function could be examined prior to its hypertrophic effects. Postnatal deletion of PTEN had no significant effect on excitatory synaptic transmission at hippocampal CA1 synapses, as basal synaptic transmission and paired pulse facilitation was normal in PTEN−/− mice compared to wild-type littermates. In contrast, deficits in both hippocampal LTP and LTD were observed in PTEN−/− mice. Postnatal deletion of PTEN also resulted in hippocampal-specific memory deficits as significant impairments in spatial memory tasks performed in the Morris water maze were observed in PTEN−/− mice. However, no differences in soma size or dendritic morphology were detected between PTEN+ and PTEN− neurons in PTEN−/− mice, suggesting that structural abnormalities do not contribute to the deficits in synaptic plasticity following postnatal PTEN deletion. As PTEN negatively regulates PI 3-kinase driven signalling, deletion or inhibition of PTEN results in uncontrolled stimulation of downstream components of the PI 3-kinase cascade, including the protein kinase PDK1. Consequently reducing PDK1 expression can reverse some neuronal abnormalities linked to PTEN deletion (Chalhoub et al. 2009). In this study, Sperow et al. examined whether postnatal deletion of PDK1 rescued the impairments in hippocampal synaptic plasticity in PTEN−/− mice. Postnatal deletion of PDK1 had no effect on hippocampal synaptic plasticity or neuronal morphology per se. However, deletion of PDK1 rescued the synaptic plasticity deficits, as the magnitude of hippocampal LTP and LTD was comparable in double mutant mice (PTEN−/−; PDK1−/−) and wild-type littermates. In contrast, however, significant impairments in spatial memory were still observed in the double mutant mice compared to wild-type littermates, suggesting that PDK1 deletion is able to counterbalance the effects of postnatal PTEN deletion on synaptic plasticity but not on spatial memory. In conclusion this study indicates that hippocampal synaptic plasticity and neuronal morphology are independently regulated by PTEN in vivo. It also highlights an important role for PTEN in hippocampal LTP and LTD. Although the precise cellular mechanisms underlying PTEN modulation of synaptic plasticity are not fully known, recent studies suggest involvement of a postsynaptic mechanism as PTEN inhibition promotes AMPA receptor trafficking to synapses leading to a persistent increase in excitatory synaptic strength in adult hippocampal slices (Moult et al. 2010). Conversely enhanced PTEN lipid phosphatase activity has been reported to depress excitatory synaptic transmission, which is in turn required for NMDA receptor-dependent LTD (Jurado et al. 2011). Together these findings provide important new insights into the role of PTEN in regulating hippocampal synaptic function.