Sujeong Yang

Depletion of perineuronal nets enhances recognition memory and long-term depression in the perirhinal cortex.

Perineuronal nets (PNNs) are extracellular matrix structures surrounding cortical neuronal cell bodies and proximal dendrites and are involved in the control of brain plasticity and the closure of critical periods. Expression of the link protein Crtl1/Hapln1 in neurons has recently been identified as the key event triggering the formation of PNNs. Here we show that the genetic attenuation of PNNs in adult brain Crtl1 knock-out mice enhances long-term object recognition memory and facilitates long-term depression in the perirhinal cortex, a neural correlate of object recognition memory. Identical prolongation of memory follows localized digestion of PNNs with chondroitinase ABC, an enzyme that degrades the chondroitin sulfate proteoglycan components of PNNs. The memory-enhancing effect of chondroitinase ABC treatment attenuated over time, suggesting that the regeneration of PNNs gradually restored control plasticity levels. Our findings indicate that PNNs regulate both memory and experience-driven synaptic plasticity in adulthood.

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

Alzheimers 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 3 month-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 1 week 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.

Neural ECM in regeneration and rehabilitation.

Neural extracellular matrix (ECM) is different from the normal ECM in other organs in that it has low fibrous protein content and high carbohydrate content. One of the key carbohydrate components in the brain ECM is chondroitin sulfate proteoglycans (CSPGs). Over the last two decades, the view of CSPGs has changed drastically, from the initial regeneration inhibitor to plasticity regulators present in the perineuronal nets to the most recent view that certain CSPG isoforms may even be growth promoters. In this chapter, we aim to address a few current progresses of CSPGs in regulating plasticity and rehabilitation in various pathological conditions in the central nervous system.

Behavioural deficits in transgenic mice expressing human truncated (1–120 amino acid) alpha-synuclein

Accumulation and aggregation of alpha-synuclein in cortical and hippocampal areas is a pathological sign for dementia with Lewy bodies (DLB) and Parkinsons disease with dementia. However the mechanisms of alpha-synuclein triggered cellular dysfunction leading to the development of memory impairment is not clear. We have created a mouse model of DLB, where aggregation-prone human truncated (120 amino acid) alpha-synuclein is expressed in forebrain areas under the calcium/calmodulin-dependent protein kinase II alpha (CamKII-alpha) promoter. We have observed the presence of the transgenic protein in target forebrain areas, with small granular cytoplasmic accumulation of aggregated alpha-synuclein. This was associated with a progressive deficit in cortical-hippocampal memory tests including the Barnes maze and novel object recognition. This data suggests that low levels of aggregation prone alpha-synuclein are sufficient to induce memory deficits in mice and that forebrain regions associated with cognitive function may have an increased sensitivity to the truncated toxic form of alpha-synuclein.

TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

Amyotrophic lateral sclerosis–frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a new approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD, leading to aberrant Mapt splicing and a paucity of parvalbumin interneurons. Phenotypic heterogeneity is exploited to yield modifiers of disease.

Progressive tauopathy in P301S tau transgenic mice is associated with a functional deficit of the olfactory system

Multiple neurodegenerative disorders with tau pathology are characterised by the loss of memory and cognitive decline that can be associated with other symptoms including olfactory alterations that are often regarded as an early symptom of the diseases. Here, we have investigated whether olfactory dysfunction is present in the P301S human tau transgenic mice and if it is associated to tau pathology. Progressive tauopathy and neurodegeneration were noticeable in the olfactory bulb and piriform cortex at early age in the P301S human tau transgenic mice and olfactory sensitivity for social or non‐social odours was significantly impaired at 3 months of age, when the piriform cortex‐dependent odour‐cross habituation was also disrupted. The olfactory alterations in the P301S tau transgenic mouse line provide an in vivo system where to test the mechanism‐based therapies for the common and yet untreatable tauopathies.

Publisher Correction: TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

In the version of this article initially published, the footnote number 17 was missing from the author list for the two authors who contributed equally. Also, the authors have added a middle initial for author Justin R. Fallon and an acknowledgement to the Babraham Institute Imaging Facility and Sequencing Core Facility. The errors have been corrected in the HTML and PDF versions of the article.