Oxidative stress is a common culprit of several conditions associated with male fertility. High levels of reactive oxygen species (ROS) promote impairment of sperm quality mainly by decreasing motility and increasing the levels of DNA oxidation. Oxidative stress is a common feature of environmental pollutants, chemotherapy and other chemicals, smoke, toxins, radiation, and diseases that can have negative effects on fertility. Peroxiredoxins (PRDXs) are antioxidant enzymes associated with the protection of mammalian spermatozoa against oxidative stress and the regulation of sperm viability and capacitation. In the present study, we aimed to determine the long-term effects of oxidative stress in the testis, epididymis and spermatozoa using the rat model. Adult male rats were treated with tert-butyl hydroperoxide (t-BHP) or saline (control group), and reproductive organs and spermatozoa were collected at 3, 6, and 9 weeks after the end of treatment. We determined sperm DNA oxidation and motility, and levels of lipid peroxidation and protein expression of antioxidant enzymes in epididymis and testis. We observed that cauda epididymal spermatozoa displayed low motility and high DNA oxidation levels at all times. Lipid peroxidation was higher in caput and cauda epididymis of treated rats at 3 and 6 weeks but was similar to control levels at 9 weeks. PRDX6 was upregulated in the epididymis due to t-BHP; PRDX1 and catalase, although not significant, followed similar trend of increase. Testis of treated rats did not show signs of oxidative stress nor upregulation of antioxidant enzymes. We concluded that t-BHP-dependent oxidative stress promoted long-term changes in the epididymis and maturing spermatozoa that result in the impairment of sperm quality.

Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder associated with autism spectrum disorder and intellectual disability, is caused by either deletions in human chromosome 22q13 or mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene. PMS is highly debilitating, and existing treatments are ineffective. SHANK3 interacts with at least 3 synaptic receptors through synaptic-associated proteins, some of which are upstream of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathways. Metformin, an inhibitor of the mTORC1 and MAPK/ERK signalling pathways, was shown to correct core phenotypes in a fragile X mouse model, offering therapeutic potential for PMS. Male Shank3B^-/-, a PMS mouse model, and wild-type mice were treated from birth with metformin (5 mg/mL) or vehicle. Shank3B^-/- mice displayed increased self-grooming, decreased social interaction, reduced duration and frequency of ultrasonic vocalisations, and impaired hippocampal-dependent memory. Upregulated mTORC1 activity was observed in the hippocampus and prefrontal cortex, along with decreased synaptosomal protein expression in the striatum of GluN2B (an N-methyl-d-aspartate receptor (NMDAR) subunit), Homer1 (a synaptic-associated protein) and GluA2 (an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit), all of which interact with Shank3. Metformin treatment from birth corrected core behavioural impairments, exaggerated mRNA translation, and decreased striatal synaptic protein expression. Considering its exceptional safety profile, metformin is a promising therapeutic option for a rapid clinical translation of PMS treatment.

Microglia interact with neurons to facilitate synapse plasticity; however, signal transducers between microglia and neuron remain unknown. Here, using in vitro organotypic hippocampal slice cultures and transient MCAO in genetically-engineered mice in vivo , we report that at 24 h post-ischemia microglia release BDNF to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the CA1 hippocampal formation in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 ^NTR and TrkB receptors respectively. Post-MCAO, we report that in the peri- infarct area and in the corresponding contralateral hemisphere similar neuroplasticity occur through microglia activation and gephyrin phosphorylation at Ser268, Ser270 in vivo . Targeted deletion of the Bdnf gene in microglia or Gphn S268A/S270A (phospho-null) point-mutations protect against ischemic brain damage, neuroinflamation and synapse downregulation normally seen post-MCAO. Collectively, we report that gephyrin phosphorylation and microglia derived BDNF faciliate synapse plasticity after transient ischemia.