Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA type A receptors (GABA Rs) are severely affected in Alzheimer's disease (AD). However, the distribution and subunit composition of GABA Rs in the AD brain are not well understood. This is the first comprehensive study to show brain region- and cell layer-specific alterations in the expression of the GABA R subunits α1-3, α5, β1-3 and γ2 in the human AD hippocampus, entorhinal cortex and superior temporal gyrus. In late-stage AD tissue samples using immunohistochemistry we found significant alteration of all investigated GABA Rs subunits except for α3 and β1 that were well preserved. The most prominent changes include an increase in GABA R α1 expression associated with AD in all layers of the CA3 region, in the stratum (str.) granulare and hilus of the dentate gyrus. We found a significant increase in GABA R α2 expression in the str. oriens of the CA1-3, str. radiatum of the CA2,3 and decrease in the str. pyramidale of the CA1 region in AD cases. In AD there was a significant increase in GABA R α5 subunit expression in str. pyramidale, str. oriens of the CA1 region and decrease in the superior temporal gyrus. We also found a significant decrease in the GABA R β3 subunit immunoreactivity in the str. oriens of the CA2, str. granulare and str. moleculare of the dentate gyrus. In conclusion, these findings indicate that the expression of the GABA R subunits shows brain region- and layer-specific alterations in AD, and these changes could significantly influence and alter GABA R function in the disease. Cover Image for this issue: doi: 10.1111/jnc.14179.

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system. Previous studies have shown fluctuations in expression levels of GABA signaling components—glutamic acid decarboxylase (GAD), GABA receptor (GABAR) subunit, and GABA transporter (GAT)—with increasing age and between sexes; however, this limited knowledge is highly based on animal models that produce inconsistent findings. This study is the first analysis of the age- and sex-specific changes of the GAD, GABAA/BR subunits, and GAT expression in the human primary sensory and motor cortices; superior (STG), middle (MTG), and inferior temporal gyrus (ITG); and cerebellum. Utilizing Western blotting, we found that the GABAergic system is relatively robust against sex and age-related differences in all brain regions examined. However, we observed several sex-dependent differences in GABAAR subunit expression in STG along with age-dependent GABAAR subunit and GAD level alteration. No significant age-related differences were found in α1, α2, α5, β3, and γ2 subunit expression in the STG. However, we found significantly higher GABAAR α3 subunit expression in the STG in young males compared to old males. We observed a significant sex-dependent difference in α1 subunit expression: males presenting significantly higher levels compared to women across all stages of life in STG. Older females showed significantly lower α2, α5, and β3 subunit expression compared to old males in the STG. These changes found in the STG might significantly influence GABAergic neurotransmission and lead to sex- and age-specific disease susceptibility and progression.

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We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.

Age-related hearing loss (ARHL) is the most common sensory disorder among older people, and yet, the treatment options are limited to medical devices such as hearing aids and cochlear implants. The high prevalence of ARHL mandates the development of treatment strategies that can prevent or rescue age-related cochlear degeneration. In this study, we investigated a novel pharmacological strategy based on inhibition of the adenosine A2A receptor (A2AR) in middle aged C57BL/6 mice prone to early onset ARHL. C57BL/6J mice were treated with weekly istradefylline (A2AR antagonist; 1 mg/kg) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4–32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies) were evaluated at 6, 9, and 12 months of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells. Cognitive function was assessed using the Morris water maze and the novel object recognition test, and the zero maze test was used to assess anxiety-like behaviour. Weekly injections of istradefylline attenuated ABR threshold shifts by approximately 20 dB at mid to high frequencies (16–32 kHz) but did not improve ABR suprathreshold responses. Istradefylline treatment improved hair cell survival in a turn-dependent manner, whilst the cognitive function was unaffected by istradefylline treatment. This study presents the first evidence for the rescue potential of istradefylline in ARHL and highlights the role of A2AR in development of age-related cochlear degeneration.