Search

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration.

Background: Intensive basic and preclinical research into Alzheimer's disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in "preclinical AD." Methods: Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in AppNL-G-F mice compared to AppNL animals which served as controls. Results: We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of AppNL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions: Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. [ABSTRACT FROM AUTHOR]