Page 57 - AN-2-3

Advanced Neurologyurology
Advanced Ne Voluntary running effects in PTEN knockout mouse

modulates protein kinase B (AKT) and its downstream Voluntary physical exercise is an intervention with
targets, such as the ribosomal protein S6 kinase (S6k) well-known benefits on brain functions, leading to
and the mechanistic target of rapamycin (mTOR). This cognitive improvement, as it increases brain activity,
regulatory mechanism regulates major cell functions, synaptic plasticity, and neurogenesis and triggers better
including cell growth, size, proliferation, survival, and performance in learning and memory [24-27] . Research has
metabolism [3-5] . revealed that physical exercise triggers the activation
of genes encoding neurotrophic factors, such as brain-
In the central nervous system (CNS), PTEN is located
in the spines and dendrites of neurons in the cerebral derived neurotrophic factor, which plays key roles in
neuroplasticity and neuronal resistance against brain
cortex, hippocampus, olfactory bulb, and cerebellum . [28,29]
[6]
Several reports provide evidence that PTEN deletion damage and neurodegenerative diseases . In addition,
results in alterations in the number, size, and migration of physical exercise is related to synaptic transmission by
cells [7-10] . Mice with deleted [7,11] or mutated [12,13] PTEN in the positively modulating NMDA receptor subunits, resulting
cerebellar granule neurons exhibit characteristics similar to in an increased expression of these subunits and their
[30]
Lhermitte-Duclos disease. This condition is characterized phosphorylated forms .
[31]
by multiple hamartomas in different tissues, which could Van Praag et al. reported that a short protocol of
lead to tumor formation. Furthermore, PTEN knockout voluntary running is sufficient to increase neurogenesis,
mice demonstrate early embryonic lethality, highlighting a finding supported by other studies as well [32,33] . More
the importance of PTEN during embryogenesis [14-17] . recently, it was reported that short-term voluntary running
can induce long-term morphological changes in synapses,
PTEN mutations are associated with mental retardation [34]
and core behaviors in autism spectrum disorders [18,19] . resulting in augmented synaptic plasticity . Therefore,
the present study aimed to investigate the effects of short-
Accordingly, PTEN deletion in mouse cortical and term voluntary running in PTEN-conditioned knockout
hippocampal neurons induced abnormal social interaction mice, focusing on behavioral (anxiety, fear memory, and
and exaggerated responses to stimuli, which were related social interaction), and biochemical aspects (glutamate
to the activation of the AKT/mTOR/S6k pathway . receptors, synaptophysin, and PTEN/AKT/S6 pathway
[19]
Moreover, PTEN knockdown in gamma-aminobutyric protein expressions).
acid neurons resulted in impaired motor coordination,
repetitive behaviors, and deficits in social and learning In our study, we observed that regardless of genotype or
abilities . Interestingly, these mice exhibited anxiety treatment, all groups spent more time in the periphery of
[20]
or anxiolytic-like behaviors depending on which PTEN an open field arena and in the closed arms of an elevated
neuronal subtype was deleted. Furthermore, loss of PTEN plus maze apparatus. In addition, fear memory was present
in cerebellar Purkinje cells also resulted in repetitive in all groups. Our findings also suggest that 10 days of
behavior and deficits in motor learning and sociability . voluntary running cannot counteract social recognition
[21]
Although the exact mechanisms remain unclear, several memory deficit in PTEN neuronal haploinsufficient mice.
reports suggest that these PTEN-behavioral deficits
occur through the activation of the AKT pathway and its 2. Materials and methods
downstream targets, such as mTOR/S6k [18-20] . 2.1. Animals and the voluntary physical exercise
At the synapse, PTEN plays an important role in protocol
plasticity. In healthy conditions, the major excitatory Pten loxp/loxp (donated by Dr. Antonio Di Cristofano from
neurotransmitter in the CNS, glutamate, binds to Albert Einstein College of Medicine, Bronx, NY, USA)
N-methyl-D-aspartate (NMDA) receptors, which are were crossed with neuron-specific enolase Nse-Cre mice
+
2+
composed of Ca -permeable channels, thus mediating (B6.Cg-Tg[Eno2-cre]39Jme/J, from Jackson Laboratory,
synaptic plasticity, excitotoxicity, learning, and memory Bay Harbor, ME, USA) to generate the Pten loxP/+ /Nse-Cre
+
formation . Research on the connection between PTEN lineage. Up to five mice were housed in Micro-Isolator
[22]
and NMDA receptors has suggested that activating plastic cages at 22 ± 2°C with a 12-h light/dark cycle at the
NMDA receptors evoke an interaction between PTEN and mouse facility of the Department of Pharmacology, Institute
postsynaptic density-95 dependent on the PDZ domain of Biomedical Sciences, University of São Paulo, São Paulo,
in the postsynaptic vesicles. This interaction is essential Brazil. All experimental procedures were approved by the
for memory consolidation, demonstrating that PTEN Ethical Committee for Animal Research of the Institute of
is required at the synapse for the modulation of NMDA Biomedical Sciences (CEUA/ICB/USP, protocol 114/2014).
receptor-dependent long-term depression and is central to In this study, we used Pten loxP/+ /Nse-Cre animals, that is,
+
excitatory synapses . heterozygous mice with PTEN deletion (HT, PTEN ).
+/-
[23]
Volume 2 Issue 3 (2023) 2 https://doi.org/10.36922/an.0872