The fate of interneurons, GABAA 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 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.

Keywords: Alzheimer's disease; GABA; Synaptic; interneurons; neurodegeneration; perineuronal nets.

FIGURE 1

(A) Schematic overview of perisomatic and dendritic inhibitory interneurons in the hippocampal CA1 subfields that show specific regional and temporal vulnerability in AD. Examples represented are: CR interneurons (pink), CCK basket and CCK Schaffer collateral‐associated cells (red), PV basket, PV axo‐axonic, PV oriens/lacunosum moleculare and PV bistratified cells (yellow), and SST oriens/lacunosum moleculare cells (violet) with respect to CA1 subfields (dotted lines). Axonal locations are shown with respect to pyramidal cells shown in blue. CA1 layers: SLM (stratum lacunosum moleculare), SR (stratum radiatum), SP (stratum pyramidale) and SO (stratum oriens). PV cells are shown enwrapped in PNNs (green). PNNs are known to be disrupted in AD. Connections do not represent the entire inhibitory network of CA1. (B) Schematic shows suggested alterations occurring at molecular level in AD. Neuroinflammation causes active microglia (pink) to release proteases that target PNNs, destabilising PV cells. This instability manifests in reduced excitability (therefore, less GABA release), increased membrane capacitance and tau protein dispersion as well as internalisation. This leads to local network hyperexcitability, hypersynchrony, increased seizure propensity and cognitive deficits. Increased and unregulated neuronal activity is implicated in tau release causing tau pathology which reciprocally affects Aβ deposition from presynaptic terminals. Loss of PV cells as well as loss of the GABA synthetic enzyme GAD67 has been reported in AD. The external Aβ build‐up integrates into cell membranes bringing on cation permeability including Ca ²⁺ which precedes oxidative stress and overall disturbed energy metabolism.