Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology

Sujeong Yang,Matthias Cacquevel,Lisa M Saksida,Timothy J Bussey,Bernard L Schneider,Patrick Aebischer,Riccardo Melani,Tommaso Pizzorusso,James W Fawcett,Maria Grazia Spillantini

doi:10.1016/j.expneurol.2014.11.013

Abstract

Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders.

Highlights

Perineuronal nets (PNNs) are extracellular matrix structures found predominantly around inhibitory parvalbumin-positive interneurons in the cortex and other brain regions
We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory
We first defined the time course of loss in spontaneous OR memory in both a transgenic mouse model of familial tauopathy, and a focal tauopathy model induced by injection of AAV containing a mutant tau cDNA

Summary

Introduction

Perineuronal nets (PNNs) are extracellular matrix structures found predominantly around inhibitory parvalbumin-positive interneurons in the cortex and other brain regions. They play a part in the termination of developmental critical periods, and their degradation restores plasticity and enhances recovery from various types of CNS damage (Frischknecht and Gundelfinger, 2012; Kwok et al, 2011; Wlodarczyk et al, 2011). While PNN digestion with chondroitinase ABC (ChABC) has enabled restoration of function after focal lesions such as stroke and spinal cord injury (Bradbury et al, 2002; Soleman et al, 2012), it is not established whether re-activation of plasticity by ChABC might restore CNS function following the diffuse neuronal loss and damage that accompanies neurodegenerative disease caused by tau pathology. The localized tauopathy in this model avoids motor confounds, which occur with damage to motoneuons in transgenic P301S tau mice after six months

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