GABAA Receptors in the Mongolian Gerbil: a PET Study Using [18F]Flumazenil to Determine Receptor Binding in Young and Old Animals

Abstract

Purpose: Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [¹⁸F]flumazenil ([¹⁸F]FMZ). Here, [¹⁸F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABA_A receptor binding capacity revealing regional differences and age-related changes.

Procedures: Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5-6 months) and 11 old (range 39-42 months) gerbils, starting simultaneously with the injection of [¹⁸F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses.

Results: BPnd differed significantly between models (p < 0.0005), showing the smallest mean difference between 2TCM as reference and SRTM as simplified procedure. SRTM revealed the lowest AIC values. Both volume of distribution (r² = 0.8793, p = 0.018) and BPnd (r² = 0.8216, p = 0.034) correlated with in vitro autoradiography data. A significant age-related decrease of receptor binding was observed in auditory (AC, IC, MGB) and other brain regions (SC and CB) (p < 0.0001, unpaired t test) being confirmed by SPM using pons as reference (p < 0.0001, uncorrected).

Conclusion: Imaging of GABA_A receptor binding capacity in gerbils using [¹⁸F]FMZ PET revealed SRTM as a simple and robust quantification method of GABA_A receptors. Comparison of BPnd in young and old gerbils demonstrated an age-related decrease of GABA_A receptor binding.

Keywords: Age-related hearing loss; Aging; Auditory system; Bio-kinetic modeling; Flumazenil; GABAA-receptor; Inhibitory neurotransmitter system.