Multiprobe molecular imaging of an NMDA receptor hypofunction rat model for glutamatergic dysfunction

Abstract

There are many indications of a connection between abnormal glutamate transmission through N-methyl-d-aspartate (NMDA) receptor hypofunction and the occurrence of schizophrenia. The importance of metabotropic glutamate receptor subtype 5 (mGluR5) became generally recognized due to its physical link through anchor proteins with NMDAR. Neuroinflammation as well as the kynurenine (tryptophan catabolite; TRYCAT) pathway are equally considered as major contributors to the pathology. We aimed to investigate this interplay between glutamate release, neuronal activation and inflammatory markers, by using small-animal positron emission tomography (PET) in a rat model known to induce schizophrenia-like symptoms. Daily intraperitoneal injection of MK801 or saline were administered to induce the model together with N-Acetyl-cysteine (NAc) or saline as the treatment in 24 male Sprague Dawley rats for one month. Biweekly in vivo [(11)C]-ABP688 microPET was performed together with mGluR5 immunohistochemistry. Simultaneously, weekly in vivo [(18)F]-FDG microPET imaging data for glucose metabolism was acquired and microglial activation was investigated with biweekly in vivo [(18)F]-PBR111 scans versus OX42 immunohistochemistry. Finally, plasma samples were analyzed for TRYCAT metabolites. We show that chronic MK801 administration (and thus elevated endogenous glutamate) causes significant tissue loss in rat brain, enhances neuroinflammatory pathways and may upregulate mGluR5 expression.

In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS

“…A subanesthetic dose of the NMDA antagonist ketamine increased [ 18 F]FDG uptake in some rat brain regions [ 40 ]. Similarly, previous rodent studies reported focal increases in [ 18 F]FDG trapping in retrosplenial and posterior cingulate cortices after a single dose of MK-801 (0.4 mk/kg) [ 41 ] and decreased [ 18 F]FDG uptake after one week of daily MK-801 administration (0.3 mg/kg) [ 42 ]. Our finding of a trend toward a global 10% increase in [ 18 F]FDG uptake (Fig.…”

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

“…The discrepancy between the TSPO and Iba-1 results could be that the [ 18 F]-PRB111 ligand lacks sufficient sensitivity to detect small changes in TSPO levels or subtle changes in neuroinflammation. Although increased [ 18 F]-PRB111 uptake has been demonstrated in several animal models of neurological diseases including epilepsy [ 144 , 145 ], multiple sclerosis [ 146 ], and schizophrenia [ 147 ], these models display extensive inflammation and postmortem pathology [ 144 – 147 ], whereas abnormalities in the HIV-1 Tat transgenic mouse model are more subtle [ 148 ] with opioid exposure inducing modest gliosis [ 29 , 149 ]. Alternatively, increases in TSPO may be most dramatic in proinflammatory “M1” microglia when initially activated and may decline with sustained activation or upon switching to a repair/remodeling “M2” phenotype [ 150 – 152 ]—although there is clearly a spectrum of functional states beyond binary M1/M2 polarization [ 153 ].…”

Longitudinal Characterization of mGluR5 Using 11C-ABP688 PET Imaging in the Q175 Mouse Model of Huntington Disease

“…Images covering the whole slices were acquired at •20 magnification with a light microscope using NIS-Elements software (version 4.2; Nikon Instruments). The mGluR5 immunoreactivity was semiquantitatively assessed by calculating the integrated optical density (23) in the regions of interest (i.e., striatum and cortex). The number of NeuN-positive neurons was quantified automatically after optimization of the sampling parameters (intensity threshold and minimum and maximum cell sizes) empirically under masked conditions (24).…”