Entorhinal cortex dysfunction in Alzheimer's disease

Abstract

The entorhinal cortex (EC) is the brain region that often exhibits the earliest histological alterations in Alzheimer's disease (AD), including the formation of neurofibrillary tangles and cell death. Recently, brain imaging studies from preclinical AD patients and electrophysiological recordings from AD animal models have shown that impaired neuronal activity in the EC precedes neurodegeneration. This implies that memory impairments and spatial navigation deficits at the initial stage of AD are likely caused by activity dysfunction rather than by cell death. This review focuses on recent findings on EC dysfunction in AD, and discusses the potential pathways for mitigating AD progression by protecting the EC.

Keywords: Alzheimer's disease; entorhinal cortex; grid cells; hippocampus; place cells.

Figure 1.. Putative time course of AD symptom progression.

A, The entorhinal-hippocampal memory circuit in the human and mouse brain. B, Hypothetical time course of AD symptom progression across three stages: preclinical, mild cognitive impairment (MCI), and dementia stages. Findings from human patients and AD animal models are putatively integrated. Aβ deposition: darker shades of pink representing greater Aβ accumulation [105]. Entorhinal cortex dysfunction: grid cell dysfunction at the preclinical stage (see Fig 3), based on findings in mouse models. Hippocampal dysfunction: Disruption of place cell remapping at the dementia stage), based on findings in mouse models (see also Fig. 4). Memory impairments: Memory impairments emerge in the MCI stage and worsen in the dementia stage. Tau pathology: Green depicts Tau accumulation starting in the EC (Braak stage I/II), spreading to the hippocampus (Braak stage III/IV) and to the cortex (Braak stage V/VI) [7]. Cell death: Neurodegeneration starts from entorhinal cortex (EC) layer 2 (L2) neurons [8, 10, 68].

Figure 2.. The entorhinal-hippocampal circuit, MEC grid cells, and LEC object + reward cells.

A, Diagram of the major connections of the mouse entorhinal-hippocampal circuit. The hippocampus receives information from the neocortex and sends information to it through the entorhinal cortex (EC). The medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC) project to CA1 through the perforant and temporoammonic paths. In the perforant path, axons of layer 2 (L2) reelin-expressing (RE+) stellate cells (MEC) and fan cells (LEC) converge on the same population of cells in the dentate gyrus (DG) and CA3, but project to distal and proximal dendrites, respectively. This mixed information in DG and CA3 is conveyed to CA1 via mossy fibers and Schaffer collaterals. By contrast, EC layer 3 (L3) pyramidal cells and calbindin-expressing (CB+) MEC layer 2 (L2) pyramidal cells form the temporoammonic pathway. Pyramidal cells in MEC largely project to proximal CA1 (prox), whereas layer III cells in LEC project to distal CA1 (dist). Output from CA1 is conveyed directly to the EC layer 5 (L5) cells, or via the subiculum. CB+ L2 pyramidal cells in the LEC, as well as L5a cells in the MEC and LEC form output axonal projection to various cortical areas, whereas L5b neurons form recurrent projections in the EC. B, In vivo electrophysiological recording of MEC grid cells in rodents. MEC Layer 2 single neurons were recorded using an implanted recording device having multiple tetrodes targeting the MEC. Spike activity was recorded for ~20 minutes while animals ran throughout an open field behavioral enclosure. Firing rate map was generated by calculating spike counts divided by time visited by the animal in each small spatial bin. Grid cells show equilateral triangular grid patterns with different spacings (grid cells #1, #2 and #3).. Modified from [18, 30, 31]. C, In vivo electrophysiological recording of LEC object + reward cells. For selectively recording LEC L2 RE+ fan cells, a cell-type-specific optogenetic-assisted electrophysiological recording technique was used [106]. Mice were trained in an odor object-reward associative memory task. When an odor (for example, banana odor) was paired with sucrose water reward, LEC L2 RE+ fan cells started to show enhanced firing, as depicted schematically in the single-neuron recording trace (top panel). By contrast (lower panel), this neuron came to exhibit decreased firing to an odor (for example, pine odor) paired with bitter quinine water. When fan cell activity was optogenetically inhibited, mice were no longer able to learn the associative memory task, indicating that LEC odor + reward cells support object memory. Modified from [49].

Figure 3.. Entorhinal cortex dysfunction in AD brains.

A, Dysfunction of MEC grid cells emerged at the preclinical period of APP knock-in mice [18]. Grid cell were defined as neurons with gridness score (GS) > ~0.4. At 3 mo, APP knock-in mice have intact spatial memory, but neurons in the MEC already lost their grid cell property. Adapted from [18]. Gridness score (GS) is a measure for repetitiveness of firing fields. B, Schematic summary of time courses of grid cell dysfunction, spatial memory deficit and pathology found in AD mouse models. Grid cell impairment was found to emerge before spatial memory impairment in APP knock-in mice [18], whereas in other transgenic mouse models grid cell impairment was found only after memory impairment [50, 57, 58]. Δ denotes impairment. C, Dysfunction of the lateral entorhinal cortex in the preclinical stage of AD patients [15]. A voxel-based analysis showed significantly lower cerebral blood volume (scale bar) in the LEC. Bottom, A higher magnification of the coronal view. TEC, transentorhinal cortex; HC, hippocampus proper; PRC, perirhinal cortex. Adapted from [15].

Figure 4.. Remapping of place cells and grid cells, and their disruption in APP knock-in mice.

Remapping of place cells and grid cells were tested using black vs. white linear tracks, and assessed by calculating spatial correlation (SC) of firing maps between two tracks. Negative spatial correlation of neurons (that is, distinct firing patterns across two tracks) denotes strong remapping, whereas positive spatial correlation (that is, similar firing patterns across two tracks) means impaired remapping. Grid cells showed remapping impairment from the preclinical stage, whereas place cells showed remapping impairment only from the dementia stage. Adapted from [18].