title: Abolished perineuronal nets and altered parvalbumin-immunoreactivity in the nucleus reticularis thalami of wildtype and 3xTg mice after experimental stroke.
abstract: Treatment strategies for ischemic stroke are still limited, since numerous attempts were successful only in preclinical research but failed under clinical condition. To overcome this translational roadblock, clinical relevant stroke models should consider co-morbidities, age-related effects and the complex neurovascular unit (NVU) concept. The NVU includes neurons, vessels and glial cells with astrocytic endfeet in close relation to the extracellular matrix (ECM). However, the role of the ECM after stroke-related tissue damage is poorly understood and mostly neglected for treatment strategies. This study is focused on alterations of perineuronal nets (PNs) as ECM constituents and parvalbumin-containing GABAergic neurons in mice with emphasis on the nucleus reticularis thalami (NRT) in close proximity to the ischemic lesion as induced by a filament-based stroke model. One day after ischemia onset, immunofluorescence-based quantitative analyses revealed drastically declined PNs in the ischemia-affected NRT from 3- and 12-month-old wildtype and co-morbid triple-transgenic (3xTg) mice with Alzheimer-like alterations. Parvalbumin-positive cells decreased numerically in the ischemia-affected NRT, while staining intensity did not differ between the affected and non-affected hemisphere. Additional qualitative analyses demonstrated ischemia-induced loss of PNs and allocated neuropil ECM immunoreactive for aggrecan and neurocan, and impaired immunoreactivity for calbindin, the potassium channel subunit Kv3.1b and the glutamate decarboxylase isoforms GAD65 and GAD67 in the NRT. In conclusion, these data confirm PNs as highly sensitive constituents of the ECM along with impaired neuronal integrity of GABAergic neurons. Therefore, specific targeting of ECM components might appear as a promising strategy for future treatment strategies in stroke.
authors.affiliation: Paul Flechsig Institute for Brain Research University of Leipzig, Liebigstr. 19, 04103 Leipzig, Germany. Electronic address: hartig@medizin.uni-leipzig.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Härtig
authors.affiliation: Paul Flechsig Institute for Brain Research University of Leipzig, Liebigstr. 19, 04103 Leipzig, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Appel
authors.affiliation: Paul Flechsig Institute for Brain Research University of Leipzig, Liebigstr. 19, 04103 Leipzig, Germany; Department of Pediatric Surgery, University Hospital Leipzig, Liebigstr. 20 A, 04103 Leipzig, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Suttkus
authors.affiliation: Effigos GmbH, Am Deutschen Platz 4, 04103 Leipzig, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Grosche
authors.affiliation: Department of Neurology, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Michalski
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008822:Mice, Transgenic; D009415:Nerve Net / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism*; D011149:Pons / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D015221:Potassium Channels
keywords: animal model; cerebral ischemia; extracellular matrix; perineuronal net; reticular thalamic nucleus; triple-transgenic mouse