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The impact of phosphorylated PTEN at threonine 366 on cortical connectivity and behaviour
Julia M T Ledderose1,2, Jorge A Benitez3, Amanda J Roberts4
1Institute for Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany.
Insights
Phosphorylation of PTEN at T366 regulates neuron size and brain circuit connectivity. This study reveals PTEN T366 signaling
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- PTEN (phosphatase and tensin homologue on chromosome 10) is a tumor suppressor and neuronal signaling regulator.
- PTEN mutations are linked to autism spectrum disorders, affecting social behavior, cognition, and sensory processing.
- PTEN's C-terminal phosphorylation sites regulate its enzymatic activity.
Purpose of the Study:
- To investigate the role of PTEN T366 phosphorylation in neuronal development and function.
- To analyze the impact of altered PTEN T366 phosphorylation on brain circuit connectivity and behavior.
- To explore the potential link between PTEN T366 signaling and autism-related neurological functions.
Main Methods:
- Generated a knock-in mouse model with Pten T366 substituted with alanine (PtenT366A/T366A).
- Conducted behavioral tests to assess cognitive and sensory functions.
- Utilized rabies virus-mediated anterograde and retrograde monosynaptic tracing to map brain circuit connectivity.
Main Results:
- PtenT366A/T366A mice exhibited cognitive deficits and selective sensory impairments, particularly in males.
- Observed restricted cellular overgrowth of cortical neurons, with increased dendritic arborization and soma size.
- Identified altered connectivity to the primary somatosensory cortex, including imbalances in long-range cortico-cortical inputs.
Conclusions:
- PTEN T366 phosphorylation is critical for controlling neuron size and brain circuit connectivity in sensory processing.
- PTEN T366 signaling influences neuronal morphology and synaptic integration.
- Dysregulation of PTEN T366 phosphorylation may contribute to specific autism-related neurological deficits.
Abstract:
The lipid phosphatase PTEN (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. PTEN mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. PTEN enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here, we focused on the role of PTEN T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A/T366A). We identify that phosphorylation of PTEN at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellular overgrowth of cortical neurons in PtenT366A/T366A brains, linked to increases in both dendritic arborization and soma size. In a combinatorial approach of anterograde and retrograde monosynaptic tracing using rabies virus, we characterize differences in connectivity to the primary somatosensory cortex of PtenT366A/T366A brains, with imbalances in long-range cortico-cortical input to neurons. We conclude that phosphorylation of PTEN at T366 controls neuron size and connectivity of brain circuits involved in sensory processing and propose that PTEN T366 signalling may account for a subset of autism-related functions of PTEN.
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