Figure 1:Transplantation of the neural stem/progenitor cells restored spatial memory learning in dementia model mice.
A. Hidden test was conducted for 4 consecutive days after visible test. Twenty-two days after neural cell transplantation, the grafted mouse showed shortening of mean platform escape latency. The improvement has become more evident 45 days after the transplantation.
B. Tracing of the swimming path of a representative mouse after neural stem/progenitor cell transplantation. The mouse swimming path was captured by CCD camera and analyzed. Total swimming time until reaching to the target platform of the grafted mice was clearly shortened after 22 days. The improvement has become more evident 45 days after the transplantation.
Video of Figure 1:
(A) Video of the trajectory of the TG mouse in the third picture from the left in the first row of Fig. 1B. It was made before transplantation in the third trial of the first day of the hidden test. The mouse was unsuccessful to reach the platform located on the near left side.
(B) Video of the the trajectory of the same TG mouse in the third picture from the left in the second row of Fig. 1B. It was made 22 days after transplantation in the third trial of the first day of the hidden test. The mouse was successful.
Histological analysis disclosed that ChAT+ neurons distributed throughout the overlying cerebral cortex around the injection site (Figure 2)ChAT+ neurons composed a quarter of the nucleated cells, of which half were human neurons, and the remaining half were mouse neurons. In the cortex of the grafted mice, half of the nucleated cells were alpha7 nAChR+ neurons. It was surprising that the distribution of cholinergic neurons and GABAergic neurons was clearly and consistently different from each other after the transplantation. We suggested that cortex-locating grafts may compensate for the depletion of Ach in the cortex, which was caused by the basal forebrain Ch4 projection loss .
Figure 2:Distribution of human neurons after transplantation of hiPS cell-derived neuronal cells in the AD model mice. The neuronal cells were initially grafted at the hilus of the DG in the mice. A couple of months later, the grafts migrated and were distributed as shown below.
A. Immunohistochemical staining of the hippocampus grafted with hiPS cell-derived neurons. Human cells were detected by antihuman nuclear protein antibody (hNuc; red). GABA producing cells were detected by anti-VGAT antibody (green). The cells were counterstained with DAPI (blue).
B. Distribution of hiPS cell-derived neurons after transplantation. Human cholinergic neurons (red) located throughout the cortex and the CA3 and CA1 of hippocampus. GABAergic neurons (green) located predominantly within the hippocampus, especially near the interface of the DG and CA3. The distribution of both cell types was clearly different from each other after the transplantation. A white rectangle in the cortex indicates the proposed area of the posterior parietal cortex, which plays a role in spatial navigation in rodents .
In the hippocampus, ChAT+ neurons were located around the injection site in the DG. In the hippocampus, one third of the nucleated cells were alpha7 nAChR+ neurons. A substantial numbers of mouse ChAT+ neurons and mouse alpha7 nAChR-expressing cells were observed in the grafted mouse hippocampus. Thus, it was possible that hiPS cell-derived neurons altered the differentiation of mouse neural stem/progenitor cells, increasing ChAT+ neurons and alpha7 nAChR expressing cells in the grafted mice. These ChAT+ neurons emerged after neuronal cell transplantation in both the cortex and hippocampus, and may contribute to the functional recovery of PDAPP mice. However, detailed analyses of the grafted mice with regard to their ChAT+ and receptor expressing neurons, especially neuronal circuits reconstituted by the grafts, are yet to be performed.
As mentioned previously, AD findings in the human GABAergic system were inconsistent, but GABAergic interneuron loss was obvious in several AD models . Impaired GABA functions were observed in PDAPP mice , tau protein transgenic mice , and apolipoprotein (apo) E 4 knock-in/APP mice . These mice exhibited defective hippocampal functions including GABAergic neuronal loss and/or dysfunction and memory deficits.
Carrying the epsilon4 allele of the apoE4 gene was a strong risk factor of AD for humans , and apoE4 directly impaired GABAergic inhibitory neuron function . GABAergic interneuron progenitors transplanted into the hippocampal hilus were functionally integrated into the host hippocampus and improved learning and memory function in apoE4 knock-in/APP mice . Thus, alteration in the inhibitory/excitatory balance may underlie the symptomatic changes in patients with AD .
Several reports supported the concept that reduction of inhibitory GABAergic synapses was associated with the pathogenesis of AD . Nonetheless, we have to be careful to understand the importance of GABA production in patients with AD. Excessive production of GABA by glial cells may have important roles for the development of neuro-inflammation, leading to neuronal cell death [61,62]. We, and others, focused on GABA-producing neurons and GABAR-expressing neurons. These differences may contribute to differences in the role of GABA in the pathogenesis of patients with AD.
We observed that the majority of VGAT-expressing cells were located around the grafted area in the hippocampus, where defective GABAergic neuronal functions were reported in the dementia model mice [63-65]. With our transplantation protocol, in order to aid reconnection with a shorter distance by axons of the graft between CA1/CA3 and DG of host, we put the cells at the hilus of the DG of the bilateral hippocampi . Thereafter, we found that VGAT+ and GABAR+ neurons were distributed in the hippocampus, especially in the hilus of the DG (Figure 2,3).
Figure 3:Possible mechanisms of GABAergic inhibitory neuron-induced beneficial effects on neuronal networks of the hippocampus in dementia model mice.
The grafts were initially put on hilus of the DG.
A. A schematic representation of VGAT/GABAR-expressing host cells in the hippocampus of normal mice.
B. A schematic representation of VGAT/GABAR-expressing host cells in the hippocampus of aged PDAPP mice. VGAT+ and GABAR+ cells decreased in number, especially in CA1 and DG subfields.
C. A schematic representation of host and human VGAT/GABARexpressing cells in the hippocampus of neuron-transplanted PDAPP mice. VGAT+ cells extend their axons both to the pyramidal cell layer (or at least the molecular layer) and the granule cell layer, to bring about re-connection of their neuronal pathways [Suzuki et al., unpublished observation].
D. A schematic representation of amyloid-beta protein deposits in the hippocampus of PDAPP mice. Synaptic spillover of GABA may act on GABAR-expressing cells and inhibit protein-mediated apoptotic neuronal cell death.
VGAT expressing cells composed 10% of the nucleated cells in the hippocampus, and more than 30% of the VGAT positive neurons were human neurons in the hippocampus of the grafted mice. GABAAR+ neurons composed 2.3% of the nucleated cells in hippocampus. In the hippocampus, more than 80% of GABAR expressing neurons were mouse cells.
Taking into account of the fact that the grafts were persistently
located near the hilus of the DG, possible mechanisms of restoration
of hippocampal cognitive functions by neuronal cell transplantation
- VGAT+ cells extend their axons both to the pyramidal cell layer (or at least molecular layer) and the granule cell layer to bring about re-connection of their neuronal pathways (Figure 5C) [67, unpublished observation].
- Synaptic spillover of GABA may act on GABAR expressing cells and inhibit protein-mediated apoptotic neuronal cell death (Figure 5D) [54,68-71].
Indeed, our preliminary experiments suggested the re-connection by the grafted VGAT positive cells with cells in the granule cell layer and cells in the pyramidal cell layer occurs either directly or indirectly . Thus, phasic inhibition of the connection among grafts and host neurons may play a crucial role in the behavioral improvement of neuron transplanted PDAPP mice. This hypothesis is consistent with the data of an association between the long-term potential impairment and increased tonic inhibition of GABA in hippocampal neurons of AD model mice [62,73-76]. Possible histological restoration by hiPS cell-derived neuronal cell transplantation into the PDAPP mouse hippocampus is shown in (Figure 3B,4), where inhibitory output provided by the hiPS derived GABAergic neurons may restore the alterations in the inhibitory/excitatory balance.
Figure 4:Possible neuronal re-connection by hiPS-derived neuronal transplantation (A part of the figure in “The synaptic organization of the Brain, ED. Gordon M, Shepherd, Oxford University Press (2003)” is modified).
A. Unique unidirectional progression of excitatory pathways (arrows) links each region in the hippocampal formation of normal mice.
B. Several neural pathways are suggested to be preferentially affected in the hippocampal formation of AD model mice (dashed lines) . Red lines indicate possible inhibitory output by the VGAT+ hiPS cell-derived neurons.
EC, Entorhinal Cortex; DG, Dentate Gyrus; CA, CornuAmmoni
We are currently investigating the possibility shown in (Figure 5), where Gutierrez suggested a possible role of CA3 interneurons in the granule cell-CA3 pyramidal cell connection .
Figure 5: Possible role of hiPS cell-derived GABAergic neurons in the grafted dementia model mice. Activation signals mediated by glutamatergic neurons may be controlled by the hiPS derived neurons (shown in green), thus, they may substitute for the CA3 interneurons lost in dementia model mice (Parts of the figure in “Gutierrez, 2016” are modified).
A. The granule cells of the DG excite pyramidal cells, through giant MF (mossy fiber) boutons. The granule cells excite CA3 interneurons to release GABA, inhibit CA3 pyramidal cells, and sustain feed-forward inhibition, through boutons en passant and filopodial extensions.
B. The granule cells of the DG excite pyramidal cells through giant MF boutons. The granule cells excite the hiPS cell-derived GABA interneuron to release GABA, inhibit pyramidal cells, and sustain feed-forward inhibition, through boutons en passant and filopodial extensions.
C. An inhibitory response in CA3 pyramidal cells after mossy fiber stimulation due to activation of CA3 interneurons.
D. An inhibitory response in pyramidal cells after mossy fiber stimulation due to activation of hiPS cell-derived GABA interneurons.
In panel A, granule cells of the DG excite pyramidal cells, through giant boutons. The granule cells excite CA3 interneurons to release GABA, inhibit pyramidal cells, and sustain feed-forward inhibition, through boutons en passant and filopodial extensions.
In panel C, an inhibitory response in pyramidal cells to mossy fiber stimulation is due to the activation of interneurons.
We agree with his proposal and taking his proposal into account, we think that our VGAT+ cells substituted the role of CA3 interneurons lost possibly by apoptosis in dementia mice (neurons colored in green in panels B and D). Our preliminary observation suggested that hiPS derived VGAT+ neurons acted on pyramidal cells located in the CA1 and CA3 (panels B and/or D).
Thus, it is possible that our neuronal cell transplantation, which supplemented GABA+/ GABAAR+ cells in the hippocampus, restored impaired GABA/GABAAR circuits in the hippocampus of the PDAPP mice, leading to the restoration of their defective cognitive functions.
In support of our findings, the importance of GABA/ GABAAR circuits was also revealed by administrations of GABA/ GABAAR modulators. NMZ, a positive allosteric modulator of GABAA function, which potentiates the function of the inhibitory neurotransmitter GABA in the brain , attenuated the glutamateinduced excitotoxic cascade leading to the inhibition of mitochondrial damage and neuronal loss [78-80].
Selective pharmacological activation of GABAA receptors has been shown to provide neuroprotection against amyloid-beta mediated toxicity, likely through the arrangement of the protein cleavage process . In vitro, chronic activation of GABAA receptor agonists protected cultured neurons against the neurotoxicity of amyloid-beta . However, treatment with picrotoxin, a GABAAR antagonist, also improved the cognitive functions of adult APP/PS1 mice .
These findings suggested that phasic and synaptic signals of substances with precise recognition of the receptors’ subunits were important for the improvement of AD memory loss.
However, glial production of GABA, possibly by inflammatory responses, may have other implications for the AD pathogenesis . Further studies are needed to clarify this.
Thus, the interaction between GABA, secreted predominantly by the grafted neurons, and receptor (GABAR) expressing grafted neurons and host neurons, may underlie the improvement of memory performance in the PDAPP mice that have undergone transplantation.
Transplantation of hiPS cell-derived neurons is a promising candidate for the treatment of advanced AD. The graft’s autonomous effects on the regeneration of damaged neuronal circuits, possibly involving ACh and GABA are attractive mechanisms for clinical application. Further studies are needed to confirm the roles of ChATpositive cells and VGAT-positive cells in functional recovery before conducting clinical application in patients with AD.
This study was partly supported by Grants-in-Aid for Scientific Research of Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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