Adeno‐associated virus‐mediated over‐expression of CREB‐regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide‐induced depression‐like behaviour in mice

Abstract

Depression is a highly complex global disabling psychiatric disorder. Unfortunately, the currently available antidepressants are not effective in a significant percentage of patients. Therefore, the underlying mechanisms of depression must be explored at the molecular level to discover new candidate molecular targets for depression treatment. Behavioural and molecular depression‐like endophenotypes have been observed in cyclic AMP response element‐binding protein‐regulated transcription coactivator 1 (Crtc1) knockout mice; however, the underlying mechanism for these endophenotypes remains unclear. This work investigated the role of hippocampal CREB‐regulated transcription coactivator 1 (CRTC1) in depression using a recombinant adeno‐associated virus (AAV) system to alter Crtc1 gene expression and explore its potential mechanism. We found that shRNA‐mediated Crtc1 gene knockdown (AAV‐shCRTC1) in the dentate gyrus regions of the ventral hippocampus directly resulted in depression‐like behaviours and down‐regulation of brain‐derived neurotrophic factor and neuropeptide VGF levels. A widely used depression model induced by lipopolysaccharide administration (0.5 mg/kg, i.p.) was applied in our study and was validated by increased immobility time in the tail‐suspension and forced swim tests and decreased sucrose consumption in the sucrose preference test. Importantly, CRTC1 over‐expression mediated by AAV‐CRTC1 in the ventral dentate gyrus regions prevented lipopolysaccharide‐induced depressive‐like behaviours, the down‐regulation of brain‐derived neurotrophic factor and VGF, and the accumulation of pro‐inflammatory cytokines such as interleukin‐6, interleukin 1‐β and tumour necrosis factor α in mice. Together, our findings indicate that CRTC1 is a key factor in depression‐like behaviour and provide an important reference for finding a novel drug target in the neuroinflammatory and neurotrophic pathways for curing depressive disorders. Cover Image for this issue: doi: .

Understanding depression: the hippocampus might hold the answer in a CREB‐regulated transcription coactivator

“…Ni et al . () extend the findings of Breuillaud et al . () and significantly advance the field with their recent study published in this issue of Journal of Neurochemistry .…”

“…The present report by Ni et al . () further shows that VGF in the hippocampus is also decreased consequent to CRTC1 knockdown.…”

AAV ablates neurogenesis in the adult murine hippocampus

“…We demonstrate that adult murine NPCs and immature neurons up to approximately 1 week of age are eliminated by rAAV in a dose-dependent fashion (Figure 1). The doses demonstrated to ablate neurogenesis are within or below the range of experimentally relevant titers commonly injected into the mouse DG, 1.5 E12 to 3.6 E13 gc/mL (Anacker et al, 2018;Castle et al, 2018;Danielson et al, 2016Danielson et al, , 2017Gong and Zhou, 2018;Hashimotodani et al, 2017;Hayashi et al, 2017;Kaspar et al, 2002;Kirschen et al, 2017;Liu et al, 2012;McAvoy et al, 2016;Ni et al, 2019;Pilz et al, 2016;Ramirez et al, 2015;Raza et al, 2017;Redondo et al, 2014;Senzai and Buzsáki, 2017;Swiech et al, 2015;Zetsche et al, 2017). This rAAVinduced cell death is rapid and persistent; BrdU-labeled cells and Tbr2+ intermediate progenitors begin to die within 12 to 18 hours post-injection and are eliminated by 48 hours (Figure 2).…”

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

“…1). The doses demonstrated to ablate neurogenesis are within or below the range of experimentally relevant titers commonly injected into the mouse DG, 1.5 E12 to 3.6 E13 gc/mL (Anacker et al, 2018;Castle et al, 2018;Danielson et al, 2016Danielson et al, , 2017Gong and Zhou, 2018;Hashimotodani et al, 2017;Hayashi et al, 2017;Kaspar et al, 2002;Kirschen et al, 2017;Liu et al, 2012;McAvoy et al, 2016;Ni et al, 2019;Pilz et al, 2016;Ramirez et al, 2013;Raza et al, 2017;Redondo et al, 2014;Senzai and Buzsáki, 2017;Swiech et al, 2015;Zetsche et al, 2017). This rAAV-induced cell death is rapid and persistent; BrdU-labeled cells and Tbr2+ intermediate progenitors begin to die within 12 to 18 hours post-injection and are eliminated by 48 hours (Fig.…”

“…Both theoretical and experimental studies indicate that the DG is involved in hippocampusdependent behavioral pattern separation and pattern completion (Chawla et al, 2005;Deng et al, 2013;Lacy et al, 2011;Leutgeb et al, 2007;Marr, 1971;McClelland et al, 1995;Treves and Rolls, 1994;Yassa and Stark, 2011). More recent studies implementing genetically encoded tools, often delivered via rAAV, provide striking evidence for the role of memory engram representations in behavioral pattern separation and completion in the DG (Bernier et al, 2017;Danielson et al, 2016;Liu et al, 2012;Ramirez et al, 2013;Redondo et al, 2014) and highlight the role of this circuit in affective disorders and stress responses (Anacker et al, 2018;Li et al, 2017;Ni et al, 2019;Ramirez et al, 2015;Shuto et al, 2018;. 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.…”