The fate of interneurons, GABAA receptor sub-types and perineuronal nets in Alzheimer's disease

Alzheimer's disease (AD) is the most common neurological disease, which is associated with gradual memory loss and correlated with synaptic hyperactivity and abnormal oscillatory rhythmic brain activity that precedes phenotypic alterations and is partly responsible for the spread of the disease pathology. Synaptic hyperactivity is thought to be because of alteration in the homeostasis of phasic and tonic synaptic inhibition, which is orchestrated by the GABA(A) inhibitory system, encompassing subclasses of interneurons and GABA(A) receptors, which play a vital role in cognitive functions, including learning and memory. Furthermore, the extracellular matrix, the perineuronal nets (PNNs) which often go unnoticed in considerations of AD pathology, encapsulate the inhibitory cells and neurites in critical brain regions and have recently come under the light for their crucial role in synaptic stabilisation and excitatory-inhibitory balance and when disrupted, serve as a potential trigger for AD-associated synaptic imbalance. Therefore, in this review, we summarise the current understanding of the selective vulnerability of distinct interneuron subtypes, their synaptic and extrasynaptic GABA(A)R subtypes as well as the changes in PNNs in AD, detailing their contribution to the mechanisms of disease development. We aim to highlight how seemingly unique malfunction in each component of the interneuronal GABA inhibitory system can be tied together to result in critical circuit dysfunction, leading to the irreversible symptomatic damage observed in AD.

Automated summary

Alzheimer's disease is a common neurological disorder characterized by memory loss and abnormal brain activity. Synaptic hyperactivity may be caused by an imbalance in phasic and tonic synaptic inhibition regulated by the GABA(A) inhibitory system and the perineuronal nets (PNNs) in the brain regions. This review summarizes the vulnerability of different types of interneurons, changes in GABA(A) receptor subtypes, and alterations in PNNs in Alzheimer's disease, highlighting their contribution to the disease mechanisms.