New article in Cerebral Cortex (2020): PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior

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 Activity

Impaired auditory fear conditioning and failed amygdala activation during retrieval in Ptentg mice. (a) Left, representative micro-CT images of the cranium of WT and Ptentg mice. Right, bar graph representing the average intracranial volume of WT and Ptentg mice measured in the micro-CT images, where N represents the number of mice and the P value was determined with a 2-tailed Mann–Whitney test (F = 1.013, DFn = 8, DFd = 6). (b) Bar graphs representing the basal PET activity in selected brain areas. All P values were determined with a 2-tailed Mann–Whitney test, N representing the number of mice: F = 3.164, DFn = 5, DFd = 8 for the frontal cortex; F = 3.061, DFn = 5, DFd = 8 for the auditory cortex; F = 3.479, DFn = 5, DFd = 8 for the dorsal hippocampus; F = 5.264, DFn = 5, DFd = 8 for the ventral hippocampus; F = 1.012, DFn = 5, DFd = 8 for the thalamus; F = 6.486, DFn = 5, DFd = 8 for the amygdala. (c) Representative coronal images of PET activity in the regions quantified in b. The bar represents the color code for the crude PET values (the sagittal and horizontal planes are presented in the Supplementary Fig. 3a). (d) Design of the combined auditory fear conditioning and PET experiment. (e) Representative images of PET activity relative to the baseline values. The bar represents the color code for the relative PET values (the sagittal and horizontal planes are presented in Supplementary Fig. 3c). (f) PET activity immediately after retrieval of the auditory fear memory in WT and Ptentg mice after baseline subtraction. All P values were determined with a 2-tailed Mann–Whitney test, with N representing the number of mice: F = 2.801, DFn = 3, DFd = 7 for the frontal cortex; F = 1.773, DFn = 3, DFd = 7 for the auditory cortex; F = 1.547, DFn = 3, DFd = 7 for the dorsal hippocampus; F = 5.597, DFn = 3, DFd = 7 for the ventral hippocampus; F = 1.903, DFn = 3, DFd = 7 for the thalamus; F = 3.854, DFn = 3, DFd = 7 for the amygdala. (g) Freezing during retrieval of auditory fear memory in WT and Ptentg mice. P value was determined with a Mann–Whitney test (F = 6.85, DFn = 15, DFd = 19), and N represents the number of mice. The data in all the graphs are the mean ± s.e.m.

https://academic.oup.com/cercor/article/30/2/505/5521615