Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus

Luna, Victor M.; Anacker, Christoph; Burghardt, Nesha S.; Khandaker, Hameda; Andreu, Valentine; Millette, Amira; Leary, Paige; Ravenelle, Rebecca; Jimenez, Jessica C.; Mastrodonato, Alessia; Denny, Christine A.; Fenton, A. G.; Scharfman, Helen E.; Hen, René

doi:10.1126/science.aat8789

Cited by 150 publications

(149 citation statements)

References 40 publications

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“…Moreover, DG activity and computations appear to depend on the addition of abDGCs (Clelland et al, 2009;Ikrar et al, 2013;Sahay et al, 2011a), which attenuate the activity of mature DGCs. This net inhibition on mature DGCs is thought to enhance pattern separation by selectively suppressing competing engrams (Espinoza et al, 2018;Johnston et al, 2016;Luna et al, 2019;McAvoy et al, 2016;Sahay et al, 2011b). Consistent with this idea, rAAV-induced ablation of neurogenesis results in a dose-dependent increase in immediate early gene activation 4 weeks after infection (Fig.…”

Section: Implications For Dg and Hippocampal Functionsupporting

confidence: 54%

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

Johnston

Parylak

Kim

et al. 2020

Preprint

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Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hours post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentate gyrus (DG)-without ablating adult neurogenesis-can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo 2photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system (CNS) should be carefully evaluated. et al., 2015). These stem cells and their immature progeny are sensitive to environmental stimuli; their proliferation, development, and survival are regulated by multiple intrinsic and extrinsic factors, including experience, stress, and inflammation (Gonçalves et al., 2016a;Kempermann et al., 2015;Monje et al., 2003;Snyder et al., 2009;Vivar et al.). Numerous studies demonstrate that abDGCs are critical for maintaining the physiological activity of mature DGCs and contribute to hippocampus-dependent behaviors (Akers et al. 17

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Section: Implications For Dg and Hippocampal Functionsupporting

confidence: 54%

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

Johnston

Parylak

Kim

et al. 2020

Preprint

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“…Our study adds to this literature by demonstrating an in vivo role for TDP-43 in neurogenesis within the adult brain. Given the importance of adultborn hippocampal neurons to spatial memory, pattern separation, mood and cognition (Sahay et al, 2011;Luna et al, 2019), impaired AHN due to TDP-43 misregulation may well have contributed to the behavioural phenotypes we previously described in mutant mice (White et al, 2018). Further studies to delineate the link between PV+ interneurons and AHN are warranted as we speculate that this will help find ways to leverage the neurogenic potential of the brain for therapeutic benefit in ALS-FTD.…”

Section: Discussionmentioning

confidence: 78%

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Lin

Kim

Ahmed

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods.Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43 Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43 Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43 Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43 Q331K knock-in mice.

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“…4S3) as well as stabilize the connection's input-output relationship 32,33 . Because this excitation-inhibition coordination depends only on MPP activation, it provides a distinct mechanism of DG excitation-inhibition coordination, complementary to that provided by immature adult-born granule cells that mediate mGluRdependent inhibition in response to LPP activation and NMDAR-dependent excitation in response to MPP activation 34 . Similar disinhibitory plasticity has also been described at the Schaffer collateral and other cortical synapses [35][36][37] .…”

Section: A Neocortical-hippocampal Subcircuit Tuned By Cognitive Traimentioning

confidence: 99%

Learning to learn persistently modifies an entorhinal-hippocampal excitatory-inhibitory subcircuit

Chung

Jou

Grau‐Perales

et al. 2019

Preprint

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SUMMARYThe neurobiology of psychological concepts like schema, and psychotherapeutic strategies of cognitive behavioral therapy (CBT) is poorly understood, partly because learning to process information confounds, and is rarely distinguished from acquiring content-specific memory. Learning to learn changes one’s overall information-processing ability, whereas neurobiological investigations typically focus on memory for content from particular experiences. We investigated entorhinal cortex-to-dentate gyrus neural circuit changes while mice learn to learn during cognitive control training (CCT) to judiciously use and ignore information. CCT changes synaptic circuit function by persistently modifying an excitatory-inhibitory interneuron subcircuit lasting weeks. CCT increases dentate gyrus expression of PKMζ that maintains long-term potentiation, particularly in somatostatin-expressing inhibitory interneurons that mediate both widespread inhibition, and through disinhibition, also local excitation of dentate gyrus. These findings that CCT modifies excitation-inhibition circuit coordination provide direct neurobiological evidence for a CBT-neuroplasticity hypothesis that, beyond particular item/event associations, learning to learn persistently changes neural circuit function.

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Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus

Cited by 150 publications

References 40 publications

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Learning to learn persistently modifies an entorhinal-hippocampal excitatory-inhibitory subcircuit

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