GABAergic Inhibitory Interneuron Deficits in Alzheimer's Disease: Implications for Treatment

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gamma-aminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. Furthermore, there is now evidence suggesting that neural network activity is aberrantly increased in AD patients and animal models due to functional deficits in and decreased activity of GABA inhibitory interneurons, contributing to cognitive deficits. Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.

Keywords: Alzheimer’s disease; GABA inhibitory interneurons; PV inhibitory interneurons; amyloid β-protein; cognitive deficits.

FIGURE 1

The role of GABA inhibitory interneurons, especially PV neurons and SST neurons, during AD progression and as potential treatment targets. Abnormal increased network activity in AD pathogenesis may be due to GABA inhibitory interneuron loss, synapse loss, or GABA inhibitory interneuron dysfunction, eventually leading to the development of the disease. GABA inhibitory interneurons are a potential target for AD treatment by increasing neuron number, enhancing neuronal activity, inhibiting synapses loss, or promoting GABA release. PV inhibitory interneurons in AD are dysfunctional with decreased γ-oscillatory activity, Nav1.1 expression, and GABA release (Verret et al., 2012). Improving Nav1.1 expression (Verret et al., 2012), enhancing γ-oscillatory activity in PV inhibitory interneurons by 40 Hz light flickering with/without 40 Hz auditory stimulation (Iaccarino et al., 2016; Adaikkan et al., 2019; Martorell et al., 2019), or transplanting Nav1.1-overexpressing interneurons (Verret et al., 2012; Martinez-Losa et al., 2018) could inhibit epileptiform phenomena and rescue cognitive deficits. Optogentic activation of PV and SST neurons rescued network oscillations (Chung et al., 2020; Park et al., 2020).

FIGURE 2

The main typical GABA inhibitory interneurons in the hippocampus involved in AD. In the CA1 region of hippocampus, it has been shown that all four types of GABA inhibitory interneuron change in number during AD. CR neurons decreased in different regions of hippocampus. The neural activity of PV neurons decreased in CA1 or/and CA3 in their corresponding studies. SST cells might also decrease in the hilus.

FIGURE 3

AD treatment through pharmacological manipulation of GABAergic transmission via GABA_A and GABA_B receptors. GABAA receptor agonists or antagonist, GABA_A receptor-positive allosteric modulators, inverse agonists of GABA_A receptor α5 subunit, agonists of α7-nAChR, inhibitors of Maob, or GABA_B receptor antagonists can rescue cognitive deficits in aged rats, AD mice, or in AD patients.