PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior

Abstract

Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior.

PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy

“…Moreover, chronic administration of the PTEN inhibitor bpV over 5 months to rTg4510 mice alleviated the synaptic and neuronal degeneration, as well as decreased microglial phagocytosis of synapses. Although several studies have shown that PTEN regulates synaptic density [29,40,67], our study is the first to reveal an involvement of PTEN in the process of synaptic elimination by microglia.…”

“…In support, we preserved levels of PSD-95 in rTg4510 mice after chronic treatment with the PTEN inhibitor bpV initiated prior to the occurrence of synapse loss. As the complement pathway functions in development and tauopathies to regulate synapse numbers [10,18,53,54], PTEN may function similarly in tauopathy as it also regulates synapse numbers during development [29,40,64].…”

“…Because there is evidence that synapse loss, including that in tauopathies, involves intracellular components of apoptosis [45], we investigated the role of the lipid and protein phosphatase PTEN in this process. PTEN has been linked to neuronal apoptosis [13] and more specifically to the homeostatic regulation of dendritic spine numbers, in that a loss of PTEN causes excessive overgrowth of spines [29], whereas its overexpression results in their dramatic loss [40,67]. PTEN activity is regulated by phosphorylation at serine (S) and threonine (T) residues which are located in its carboxyterminal domain.…”

MERLIN: a novel BRET-based proximity biosensor for studying mitochondria–ER contact sites

“…Primary neurons in culture were prepared from E18 Sprague Dawley rat hippocampi as described by Sanchez-Puelles et al (2019). Hippocampi were dissected and dissociated using trypsin (0.25%) and DNase I (0.1 mg/ml) and further subjected to mechanical trituration.…”

Network pharmacology study on the mechanism of the herb pair of prepared Rehmannia root-Chinese arborvitae kernel for anxiety disorders

“…In addition, it also plays a role in synaptic plasticity in adulthood. Studies have shown that the synaptic function of PTEN in amygdala is closely related to specific behavioral characteristics (47).…”