Abstract
Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation.
Highlights
Postnatal brain development is a critical period during which synaptic connections are formed and refined
To confirm that the proteasome had been inhibited, chymotrypsin proteasomal activity was measured in the brains of PD10 mice treated with proteasome inhibitors
The number of neurons in the hippocampus labelled for DCX was significantly lower in adult mice treated postnatally with proteasome inhibitors than in control animals (Fig. 7B). These results suggest that mice treated with proteasome inhibitors during postnatal development experience premature neuronal loss in the hippocampus and amygdala, which may account for the impaired cognitive abilities observed
Summary
Postnatal brain development is a critical period during which synaptic connections are formed and refined. Rats exposed to neurotoxic compounds during the first few weeks of postnatal development display spontaneous recurrent seizure activity upon reaching adulthood, evident both behaviourally and in electroencephalographic analyses [8,9]. Exposure to such toxins provokes the formation of a hyperexcitable hippocampal network in vitro [10,11]. Deprivation of maternal care during the first week of life provokes emotional and cognitive behavioural alterations in rodents that are manifested in adults [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
