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

Abstract

The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase-and protein synthesis-dependent forms of synaptic plasticity, theta burstinduced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young NseCre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.T he discovery of genes associated with autism spectrum disorders (ASDs) has largely depended on gene linkage analyses within lineages of humans with familial ASDs (1-3). A well-established candidate gene is the tumor-suppressor gene, phosphatase and tensin homolog missing on chromosome 10 (PTEN) (4-7). Pten is a lipid and protein phosphatase best known for its role in suppressing tumor formation by inhibiting cellular survival, proliferation, and cellular architecture (8, 9), but which also plays an important role in brain morphology and synaptic function (10, 11). Pten acts via its lipid phosphatase activity to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate and negatively regulate the PI3K-mammalian target of rapamycin (mTOR) signaling pathway. Although PTEN mutations are present in 5-10% of people with ASDs (12-14), loss-of-function point mutations in this gene give rise to progressive macrocephaly, a hallmark feature that occurs in nearly 20% of humans with ASDs (5, 6). In addition to anatomical abnormalities, humans with inactivating PTEN mutations exhibit spontaneous seizures and deficits in social and cognitive behaviors (10, 11).A conditional Pten knockout mouse (cKO) in which both alleles of the Pten gene contain loxP sites and Cre recombinase (Cre) is expressed under the neuron-specific enolase promoter (Nse-Cre) provides a clinically relevant mouse model for humans with inactivating PTEN mutations (15). In Nse-Cre Pten cKO (hereafter P...

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

“…An increase in excitatory transmission in PTEN-KO models is well documented in several studies in different types of neuronal cells (Luikart et al, 2011;Takeuchi et al, 2013). Here we report for the first time in PTEN-KO PCs an increased amplitude of EPSCs evoked by stimulation of the PF-PC synapse.…”

Activity-dependent PI(3,5)P 2 synthesis controls AMPA receptor trafficking during synaptic depression

“…For example, clathrin-mediated endocytosis of AMPARs, which is regulated by PI(4,5)P 2 and the 5-phosphatase synaptojanin (43), are critical for internalization of AMPARs during synaptic depression (88). Dynamic changes in the metabolism of PI(4,5)P 2 (88,89) and PI(3,4,5)P 3 (46,90,91) are critical for LTD and other forms of synaptic plasticity (reviewed in ref. 92).…”

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

“…The picture muddies somewhat in the details, recent examples being the directionality of Pten regulation or how phenotypes manifest in conditional knockouts (cKOs) compared with germline disruption models [61][62][63][64][65]. The 1998 discovery that homozygous deletion of Pten in mice causes embryonic lethality by embryonic day 7.5 directed many groups toward homozygous cKOs to investigate Pten functions in the CNS [66].…”

“…Several reports indicate that PTEN inhibition of PI3K is essential for LTD, with conflicting reports on its requirement in LTP [42,63]. This role in synaptic plasticity may be disconnected from PTEN regulation of cell size and morphology, as multiple reports indicate that functional deficits arise prior to neuronal hypertrophy [64,65]. The baseline electrical activity of PTEN-null neurons also appears to be altered in favor of increased excitatory postsynaptic current, as measured in both the hippocampus and basolateral amygdala [75,76].…”