Alzheimer's disease (AD) is a primary neurodegenerative disease that is highly prevalent in the elderly. With the advent of an aging society, AD has become a major current and future global public health problem, placing a heavy burden on family caregivers and healthcare systems (Patterson, 2018). However, new treatments for AD have been difficult to develop, and even recently approved AD drugs remain controversial. For example, aducanumab and lecanemab, which are monoclonal antibodies targeting amyloid-β (Aβ), have shown improvements in cognition and biomarker outcomes. However, aducanumab has been questioned for its overall efficacy and lecanemab for its mixed results in clinical trials (Shi et al., 2022; Jeremic et al., 2023). Thus, there is an unmet need for further research into effective AD drugs and novel therapeutic targets.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). There are two types of GABA receptors in the CNS: ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors (Matsumoto, 1989). GABAC receptors and their relationship to cognition are rarely studied in AD. However, on the one hand, accumulating evidence suggests that GABAA-mediated inhibition plays an important role in the pathobiology of AD and that GABAA receptors may be a potential target for AD treatment (Rissman and Mobley, 2011; Lei et al., 2016; Fu et al., 2019; Ghit et al., 2021; Sakimoto et al., 2021). On the other hand, recent evidence suggests that GABAB-mediated inhibition is an important contributor to AD pathobiology, and GABAB receptors appear to be a suitable target for more effective drugs to treat the cognitive symptoms of AD (Vlachou, 2022). Changes in GABAB receptors have been found at a time point consistent with AD-related deficits (Salazar et al., 2021). In addition, GABAB receptors have been identified as a leading candidate synaptic receptor for soluble amyloid-beta (Aβ) precursor protein (APP) (Rice et al., 2019). The soluble APP fragments could bind to presynaptic GABAB receptors and lead to a decrease in neurotransmitter release, subsequently modulating synaptic transmission and plasticity (Rice et al., 2019). Furthermore, the use of a specific presynaptic GABAB regulator could rescue the hyperexcitation of neurons in APP-overexpressing animals (Kreis et al., 2021).

Previously, very low doses of GABAA acting-drugs were reported to improve spatial memory, accompanied by recovery of brain rhythm in local brain regions such as the prefrontal cortex (PFC) (Fu et al., 2019). In the present study, we aimed to determine what changes in cognitive function and brain activity occur in AD animals in the case of GABAB regulation. Baclofen, as a prototypical GABAB receptor agonist, is commonly used to assess the role of the receptor in various behavioral processes (Bowery et al., 2002). In this study, AD animals were treated with various doses of baclofen and showed behavioral improvement. We further evaluated the effects of baclofen on brain activity using EEG techniques. The GABAB receptor antagonist phaclofen was also used for comparison. To date, there have been very few studies of baclofen and phaclofen in AD animals, particularly in relation to brain electrical activity. This study should improve our understanding of the relationship between GABAB receptors and cognitive decline in AD.