Structural Plasticity of the Hippocampus in Neurodegenerative Diseases

Abstract

Neuroplasticity is the capacity of neural networks in the brain to alter through development and rearrangement. It can be classified as structural and functional plasticity. The hippocampus is more susceptible to neuroplasticity as compared to other brain regions. Structural modifications in the hippocampus underpin several neurodegenerative diseases that exhibit cognitive and emotional dysregulation. This article reviews the findings of several preclinical and clinical studies about the role of structural plasticity in the hippocampus in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In this study, literature was surveyed using Google Scholar, PubMed, Web of Science, and Scopus, to review the mechanisms that underlie the alterations in the structural plasticity of the hippocampus in neurodegenerative diseases. This review summarizes the role of structural plasticity in the hippocampus for the etiopathogenesis of neurodegenerative diseases and identifies the current focus and gaps in knowledge about hippocampal dysfunctions. Ultimately, this information will be useful to propel future mechanistic and therapeutic research in neurodegenerative diseases.

Keywords: hippocampal function; neurodegenerative diseases; neuroplasticity; structural plasticity.

Figure 1

Schematic flow diagram of the correlation between etiopathogenesis and hippocampal synaptic dysfunction in neurodegenerative diseases. In neurodegenerative diseases, several etiological factors impact hippocampal synaptic plasticity, leading to functional outcomes such as cognition and emotional dysregulations. Abbreviations: Ach, acetylcholine; A2AR, adenosine A_2A receptor; AD, Alzheimer’s disease; α-Syn, alpha-synuclein; Aβ, amyloid beta; ALS, amyotrophic lateral sclerosis; BDNF, brain-derived neurotrophic factor; DA, dopamine; EPSC, excitatory post-synaptic current; FTD, frontotemporal dementia; Glu, glutamate; HD, Huntington’s disease; HPtau, hyperphosphorylated Tau; IC, inflammatory cells; IM, inflammatory mediators; LTD, long term depression; LTP, long term potentiation; mhtt, mutant-huntingtin; MS, multiple sclerosis; NA, noradrenaline; NFTs, neurofibrillary tangles; NMDAR, N-methyl-D-aspartate receptors; NTs, neurotransmitter systems; PD, Parkinson’s disease; PSD, post-synaptic density; PTP, post-tetanic potentiation; ROS, reactive oxygen species; VD, vascular dementia.

Figure 2

Schematic illustration of proposed mechanistic pathways for alteration of structural plasticity in the hippocampus in neurodegenerative diseases. During neurodegenerative diseases, pathological proteins, inflammation, neurotransmitter imbalance, impaired energy production, genetic factors, and activation of kinases affect the actin cytoskeleton and/or microtubule arrangement through different pathways. Abbreviations: AD, Alzheimer’s disease; α-Syn, alpha-synuclein; Aβ, amyloid-β; ATP, Adenosine 5′-triphosphate; BDNF, brain-derived neurotrophic factor; DA, dopamine; FTD, frontotemporal dementia; Glu, glutamate; GluR, glutamate receptor; GSK-3β, glycogen synthase kinase3β; HD, Huntington’s disease; IFNγ, interferon γ; IL-1β, interleukin 1β; LRRK2, leucine-rich repeat kinase 2; LIMK1, LIM kinase 1; MAPT, microtubule-associated tau; MS, multiple sclerosis; NA, noradrenaline; NT, neurotransmitter; PAK1, P21 (RAC1) Activated Kinase 1; PD, Parkinson’s disease; PSD, post-synaptic density; HPtau, hyperphosphorylated Tau; Rac1, Ras-related C3 botulinum toxin substrate 1; TNFα, tumor necrosis factor α; TrkB, tyrosine receptor kinase B; VD, vascular dementia.