Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities

Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function. KeywordsPTEN; PI3K; brain; neurons; myelin; hypertrophy; synaptic plasticityThe tumor suppressor PTEN (phosphatase and tensin homolog, deleted on chromosome 10) is important in the modulation of cell growth, proliferation and survival. Inactivating mutations in both alleles of PTEN occur in diverse tumor types including glioblastoma multiforme (Chow and Baker, 2006). Consistent with the two-hit hypothesis of tumor suppression, inherited mutations in PTEN are associated with cancer predisposition, and the second allele of PTEN *To whom correspondence should be addressed: Suzanne.Baker@stjude.org; Phone: (901) 495-2254; FAX: (901) 495-2270. Section Editor: John L.R. Rubenstein, Developmental Neuroscience Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof bef...

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism

“…Whereas mice used in the present study exhibit ablation of Pten primarily in DGCs and CA3, but not CA1, pyramidal neurons, in the hippocampus, CaMKIIα-Cre Pten and Pten +/− cKO mice exhibit reduced expression of Pten primarily in CA1 pyramidal neurons. Whereas CaMKIIα-Cre Pten cKO exhibit cognitive, but not morphological, abnormalities before their death at ∼11 wk (37), GFAP-Cre Pten cKO and Pten +/− mice exhibit morphological abnormalities, but not cognitive deficits (38)(39)(40). Thus, our findings extend the work of others in that we document deficits in LTP and LTD at DGC synapses in a clinically relevant model of Pten inactivation.…”

“…Moreover, our observation that marked alterations in synaptic function coincide with and/or precede the onset of behavioral deficits is consistent with the concept of "synaptic failure," postulated to be a causal factor in the dementia associated with Alzheimer's disease (36). Synaptic plasticity deficits have been reported at CA1, but not DGC, synapses of other mouse models of Pten inactivation, including calcium/calmodulin dependent protein kinase II α (CaMKIIα)-Cre Pten cKO mice (37), GFAP-Cre Pten cKO mice (38), and Pten +/− mice (39,40). Whereas mice used in the present study exhibit ablation of Pten primarily in DGCs and CA3, but not CA1, pyramidal neurons, in the hippocampus, CaMKIIα-Cre Pten and Pten +/− cKO mice exhibit reduced expression of Pten primarily in CA1 pyramidal neurons.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Indeed, deletion of Pten in multiple neuronal types during development results in profound defects in migration and patterning in brain (Backman et al, 2001;Groszer et al, 2001;Kwon et al, 2001;Marino et al, 2002;Yue et al, 2005). Finally, abnormalities in synaptic structure have been identified in LDD patients, as well as Pten conditional knockout mice (Kwon et al, 2006;Fraser et al, 2008). Thus, the abnormalities observed in LDD can be attributed to key roles of PTEN in neuronal migration, size regulation and specialized subcellular structure.…”

“…Alternatively, it is possible that individual variation in other regulators of PI3K signaling may cause neurological dysfunction in the context of PTEN haploinsufficiency. Experimental systems have shown that loss of Pten function can have profound consequences on patterning in the brain, proper neuronal morphogenesis and function, as well as defects in myelination (Fraser et al, 2008;van Diepen and Eickholt, 2008), showing remarkably specialized functions for a pathway that is ubiquitously expressed and evolutionarily conserved.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Synaptic structures throughout the cortex and cerebellum were enlarged, and axons showed evidence of severe myelin thickening. Loss of PTEN expression also resulted in the development of decreased synaptic functionality, or weakening of both synaptic transmission and synaptic plasticity within the hippocampus [37,38].…”