PTENα Modulates CaMKII Signaling and Controls Contextual Fear Memory and Spatial Learning

Abstract

PTEN (phosphatase and tensin homology deleted on chromosome 10) has multiple functions, and recent studies have shown that the PTEN family has isoforms. The roles of these PTEN family members in biologic activities warrant specific evaluation. Here, we show that PTENα maintains CaMKII in a state that is competent to induce long-term potentiation (LTP) with resultant regulation of contextual fear memory and spatial learning. PTENα binds to CaMKII with its distinctive N terminus and resets CaMKII to an activatable state by dephosphorylating it at sites T305/306. Loss of PTENα impedes the interaction of CaMKII and NR2B, leading to defects in hippocampal LTP, fear-conditioned memory, and spatial learning. Restoration of PTENα in the hippocampus of PTENα-deficient mice rescues learning deficits through regulation of CaMKII. CaMKII mutations in dementia patients inhibit CaMKII activity and result in disruption of PTENα-CaMKII-NR2B signaling. We propose that CaMKII is a target of PTENα phosphatase and that PTENα is an essential element in the molecular regulation of neural activity.

PTENα regulates endocytosis and modulates olfactory function

“…PTENa is highly expressed in the mouse OB, and levels of its expression vary temporally Preliminary data from our laboratory showed that PTENa is expressed in different regions of the brain in mice (22). However, distribution of PTENa expression varies over these different brain regions.…”

“…The PTENa-specific knockout mouse model (Ptena mu/mu mice) used in this study is generated as previously described (22). Briefly, mouse embryonic stem cells were electroporated with a knockin-targeting construct designed to replace 347CTG and 362CTG of the PTEN gene with GGA.…”

“…Pull-down assays were conducted as previously described (22). Briefly, exogenous proteins were expressed in HEK293T cells, pulled down by S-tag agarose or FLAG agarose, and incubated with mouse OB tissue lysate at 4°C for 3 h. The proteins were then eluted from agarose with glycine-HCl buffer (pH = 3.5), neutralized with Tris-HCl buffer (pH = 8.0), and subjected to mass spectrometry.…”

“…PTENa translates from the 59UTR region of the same mRNA as PTEN, containing an evolutionarily conserved 173-aa N-terminal extension (20,21). Recently, PTENa is shown to play important roles in maintenance of mitochondrial structure and energy metabolism (21), modulation of hippocampal long-term potentiation and processes of learning and memory (22), regulation of cardiac homeostasis and mitophagy (23,24), and promotion of type I IFN responses and antiviral immunity (25). However, it likely has other biologic functions that have not been characterized.…”

“…Our preliminary data showed that PTENa is expressed predominantly in the OB of the mouse brain. In view of the fact that PTENa plays important roles in modulation of neural activity (22), we sought to determine whether PTENa and olfactory function are linked.…”