Perineuronal nets and their role in cognitive impairment in central nervous system diseases

• Author / Creator

  Paylor, John W

• Perineuronal nets (PNNs) are organized components of the extracellular matrix that surround mature neurons of the central nervous system (CNS). These structures have neuroprotective properties for host cells, provide structural and functional stability, and have been implicated in brain functions such as learning and memory. This is particularly relevant given that the loss of PNNs is observed in diseases of the CNS, such as schizophrenia and Alzheimer’s disease, which also feature cognitive impairment. Given these observations, there is great interest into identifying animal models of disease which feature similar PNN deficits as the human condition, as they could be utilized to further evaluate the significance of their loss.
  In my first experiment, I evaluated PNN deficits in the 5xFAD mouse model of Alzheimer’s disease. This model features amyloid-β deposition, neuroinflammation, cell loss, and cognitive impairments in tests of memory. I show that 7- and 11-month-old animals have PNN deficits in three of five brain regions examined, including the primary motor cortex, CA1 of the hippocampus, and retrosplenial cortex. I also present data showing that 7-month-old animals have an impairment in memory function. A strength of this work is its evaluation of PNN integrity across numerous brain regions, whereas a focus on a single region is a limitation of other studies in this field. Together, our findings and others indicate that the 5xFAD model exhibits PNN deficits and support is use in evaluating the mechanisms of PNN loss in AD.
  In my second experiment, I address a limitation of PNN studies in animal models of disease, which is the presence of the confounding factors of disease pathophysiology. Joint observations of PNN deficits and cognitive impairment in these models cannot provide causative evidence that PNN loss contributes to these impairments. Thus, in this study I sought to degrade PNNs locally within the medial prefrontal cortex of rats to evaluate the impact on cognitive function. My results show that PNN degradation within the mPFC results in impairment in two tests of working memory. PNN degradation however did not impact behavioural flexibility or sensorimotor gating, and the integrity of PV+ interneurons or local inhibitory connectivity was unaltered. These results demonstrate that outside of the confounds of disease models, localized disruption of PNNs within the medial prefrontal cortex can impact cognitive function.
  Finally, I evaluate the impact of PNN degradation in the medial prefrontal cortex and retrosplenial cortex of mice on four behavioural assessments designed to assess memory function. To degrade PNNs, I utilized a viral vector system called dox-i-ChABC which expressed ChABC under the control of a dietary trigger. This design enabled behavioural assessments at baseline, after 30 days of ChABC expression, and a subsequent 30 days after the trigger for ChABC had been withdrawn. My results indicate that PNN degradation at either site had minimal impact on cognitive performance. In animals with PNN degradation in the RSC, there was subtle impairments in performance on the crossmodal object recognition task and a loss of PV+ interneurons, although these animals also exhibited changes in exploratory behaviour which could have impacted their performance. I also evaluate the impact of PNN degradation on cortical activity patterns using wide field calcium imaging. PNN degradation left cortical activity and connectivity largely unaltered, although there were decreases in the power of low frequency activity within the RSC. Together, these experiments show that PNN degradation in the RSC of mice has subtle impacts on cognition and cortical activity.
  In summary, my work shows PNN deficits in a prominent animal model of AD and shows that it may be useful in further evaluations into PNN deficits and AD. I show mixed evidence of PNNs involvement in several tests of cognitive function, which varies by the region affected and animal species. I demonstrate that PNN loss does not have an immediate effect on the integrity of closely associated PV+ cells, but that prolonged degradation can. PNN degradation also decreased the power of low frequency activity generated from the RSC. These works offer added description to the impacts of PNN degradation on cognition, PV+ interneurons, and broader patterns of cellular activity. These findings are particularly relevant for diseases such as Alzheimer’s and schizophrenia, which feature both PNN loss and cognitive impairment.

• Subjects / Keywords

  • Perineuronal net
  • Schizophrenia

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-m41s-x641

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.