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

Abstract

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 excitatoryinhibitory 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.

Linking Social Cognition, Parvalbumin Interneurons, and Oxytocin in Alzheimer’s Disease: An Update

“…The impaired function of PV interneurons in hippocampal CA2 is accompanied by reduced inhibitory control in CA2, resulting in hyperexcitability of the pyramidal neurons and social memory deficits in Tg2576 mice [27]. This finding follows the general view that poor inhibitory transmission results in hyperexcitability of pyramidal cells, further lead-ing to neurotoxicity and neuronal loss [103]. The PV interneuron damage progression in AD is illustrated in Fig.…”

The Role of Cerebellar Intrinsic Neuronal Excitability, Synaptic Plasticity, and Perineuronal Nets in Eyeblink Conditioning

“…This could explain the decreases in membrane excit- There has been much less discussion about the role of the PNN in intrinsic membrane excitability. Theorizing about the function of the PNN includes regulating the localization of ion channels [249,250], binding cations [251], gating ion channels [252], anchoring ion channels, ion exchangers, and ion transporters in the plasma membrane, as well as reducing membrane capacitance by acting as an electrostatic insulator [253]. PNNs may act as local buffers of sodium and potassium ions in the extracellular space to ensure rapid ion transport [254,255].…”

Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer’s Disease

“…Although some studies suggest that GABAergic neurons are more resistant to neurodegeneration in AD [121,122] relative to cholinergic and glutamatergic neurons, others have reported that aberrant brain GABA levels are present in AD and mood disorders as well as in normal ageing [123][124][125][126]. Furthermore, evidence suggests a selective vulnerability of inhibitory interneurons during the disease progression of AD [127,128]. Therefore, there is scope for the development of drugs that can preferentially bind to specific subunits of the GABA A R family that will have fewer ADRs than the current benzodiazepines used clinically.…”