scholarly journals Increased abundance of nuclear HDAC4 impairs neuronal development and long-term memory

2021 ◽  
Author(s):  
Patrick Main ◽  
Wei Jun Tan ◽  
David Wheeler ◽  
Helen L Fitzsimons
Keyword(s):  
Subcellular Distribution ◽  
Mushroom Body ◽  
Neuronal Development ◽  
Eye Development ◽  
Critical Role ◽  
Long Term Memory ◽  
Term Memory ◽  
Neuronal Nuclei ◽  
Transcriptional Changes

AbstractDysregulation of the histone deacetylase HDAC4 is associated with both neurodevelopmental and neurodegenerative disorders, and a feature common to many of these disorders is impaired cognitive function. HDAC4 shuttles between the nucleus and cytoplasm in both vertebrates and invertebrates and alterations in the amounts of nuclear and/or cytoplasmic HDAC4 have been implicated in these diseases. In Drosophila, HDAC4 also plays a critical role in the regulation of memory however the mechanisms through which it acts are unknown. Nuclear and cytoplasmically-restricted HDAC4 mutants were expressed in the Drosophila brain to investigate a mechanistic link between HDAC4 subcellular distribution, transcriptional changes and neuronal dysfunction. Deficits in mushroom body morphogenesis, eye development and long-term memory correlated with increased abundance of nuclear HDAC4 but were associated with minimal transcriptional changes. Although HDAC4 sequesters MEF2 into punctate foci within neuronal nuclei, no alteration in MEF2 activity was observed on overexpression of HDAC4, and knockdown of MEF2 had no impact on long-term memory, indicating that HDAC4 is likely not acting through MEF2. Similarly, deletion of the MEF2 binding site also had no impact on HDAC4-induced impairments in eye development, however it did significantly reduce the mushroom body deficits, thus nuclear HDAC4 acts through MEF2 to disrupt mushroom body development. These data provide insight into the mechanisms through which dysregulation of HDAC4 subcellular distribution impairs neurological function and provides new avenues for further investigation.

scholarly journals Increased Abundance of Nuclear HDAC4 Impairs Neuronal Development and Long-Term Memory

2021 ◽  
Vol 14 ◽  
Author(s):  
Patrick Main ◽  
Wei Jun Tan ◽  
David Wheeler ◽  
Helen L. Fitzsimons
Keyword(s):  
Binding Site ◽  
Subcellular Distribution ◽  
Mushroom Body ◽  
Neuronal Development ◽  
Eye Development ◽  
Critical Role ◽  
Long Term Memory ◽  
Term Memory ◽  
Transcriptional Changes

Dysregulation of the histone deacetylase HDAC4 is associated with both neurodevelopmental and neurodegenerative disorders, and a feature common to many of these disorders is impaired cognitive function. HDAC4 shuttles between the nucleus and cytoplasm in both vertebrates and invertebrates and alterations in the amounts of nuclear and/or cytoplasmic HDAC4 have been implicated in these diseases. In Drosophila, HDAC4 also plays a critical role in the regulation of memory, however, the mechanisms through which it acts are unknown. Nuclear and cytoplasmically-restricted HDAC4 mutants were expressed in the Drosophila brain to investigate a mechanistic link between HDAC4 subcellular distribution, transcriptional changes and neuronal dysfunction. Deficits in mushroom body morphogenesis, eye development and long-term memory correlated with increased abundance of nuclear HDAC4 but were associated with minimal transcriptional changes. Although HDAC4 sequesters MEF2 into punctate foci within neuronal nuclei, no alteration in MEF2 activity was observed on overexpression of HDAC4, and knockdown of MEF2 had no impact on long-term memory, indicating that HDAC4 is likely not acting through MEF2. In support of this, mutation of the MEF2 binding site within HDAC4 also had no impact on nuclear HDAC4-induced impairments in long-term memory or eye development. In contrast, the defects in mushroom body morphogenesis were ameliorated by mutation of the MEF2 binding site, as well as by co-expression of MEF2 RNAi, thus nuclear HDAC4 acts through MEF2 to disrupt mushroom body development. These data provide insight into the mechanisms through which dysregulation of HDAC4 subcellular distribution impairs neurological function and provides new avenues for further investigation.

scholarly journals Drosophila Graf regulates mushroom body β-axon extension and olfactory long-term memory

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sungdae Kim ◽  
Joohyung Kim ◽  
Sunyoung Park ◽  
Joong-Jean Park ◽  
Seungbok Lee
Keyword(s):  
Mushroom Body ◽  
Neuronal Development ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Long Term Memory ◽  
Loss Of Function ◽  
Specific Expression ◽  
Term Memory

AbstractLoss-of-function mutations in the humanoligophrenin-1(OPHN1) gene cause intellectual disability, a prevailing neurodevelopmental condition. However, the role OPHN1 plays during neuronal development is not well understood. We investigated the role of theDrosophilaOPHN1 ortholog Graf in the development of the mushroom body (MB), a key brain structure for learning and memory in insects. We show that loss of Graf causes abnormal crossing of the MB β lobe over the brain midline during metamorphosis. This defect inGrafmutants is rescued by MB-specific expression of Graf and OPHN1. Furthermore, MB α/β neuron-specific RNA interference experiments and mosaic analyses indicate that Graf acts via a cell-autonomous mechanism. Consistent with the negative regulation of epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) signaling by Graf, activation of this pathway is required for the β-lobe midline-crossing phenotype ofGrafmutants. Finally,Grafmutants have impaired olfactory long-term memory. Our findings reveal a role for Graf in MB axon development and suggest potential neurodevelopmental functions of human OPHN1.

scholarly journals Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Pierre-Yves Plaçais ◽  
Éloïse de Tredern ◽  
Lisa Scheunemann ◽  
Séverine Trannoy ◽  
Valérie Goguel ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Mushroom Body ◽  
Long Term Memory ◽  
Term Memory

scholarly journals Long-term memory requires sequential protein synthesis in three subsets of mushroom body output neurons in Drosophila

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Jie-Kai Wu ◽  
Chu-Yi Tai ◽  
Kuan-Lin Feng ◽  
Shiu-Ling Chen ◽  
Chun-Chao Chen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mushroom Body ◽  
Long Term Memory ◽  
Term Memory ◽  
Output Neurons

scholarly journals The Medial Temporal Lobe Is Critical for Spatial Relational Perception

2020 ◽  
Vol 32 (9) ◽  
pp. 1780-1795 ◽  
Author(s):  
Nicholas A. Ruiz ◽  
Michael R. Meager ◽  
Sachin Agarwal ◽  
Mariam Aly
Keyword(s):  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Critical Role ◽  
Long Term Memory ◽  
Term Memory ◽  
Cognitive Domains ◽  
Attention Tasks ◽  
Human Participants ◽  
Attention And Perception

The medial temporal lobe (MTL) is traditionally considered to be a system that is specialized for long-term memory. Recent work has challenged this notion by demonstrating that this region can contribute to many domains of cognition beyond long-term memory, including perception and attention. One potential reason why the MTL (and hippocampus specifically) contributes broadly to cognition is that it contains relational representations—representations of multidimensional features of experience and their unique relationship to one another—that are useful in many different cognitive domains. Here, we explore the hypothesis that the hippocampus/MTL plays a critical role in attention and perception via relational representations. We compared human participants with MTL damage to healthy age- and education-matched individuals on attention tasks that varied in relational processing demands. On each trial, participants viewed two images (rooms with paintings). On “similar room” trials, they judged whether the rooms had the same spatial layout from a different perspective. On “similar art” trials, they judged whether the paintings could have been painted by the same artist. On “identical” trials, participants simply had to detect identical paintings or rooms. MTL lesion patients were significantly and selectively impaired on the similar room task. This work provides further evidence that the hippocampus/MTL plays a ubiquitous role in cognition by virtue of its relational and spatial representations and highlights its important contributions to rapid perceptual processes that benefit from attention.

scholarly journals Drosophila ORB protein in two mushroom body output neurons is necessary for long-term memory formation

2013 ◽  
Vol 110 (19) ◽  
pp. 7898-7903 ◽  
Author(s):  
T.-P. Pai ◽  
C.-C. Chen ◽  
H.-H. Lin ◽  
A.-L. Chin ◽  
J. S.-Y. Lai ◽  
...  
Keyword(s):  
Mushroom Body ◽  
Memory Formation ◽  
Long Term Memory ◽  
Term Memory ◽  
Output Neurons

scholarly journals Systematic functional characterization of the intellectual disability-associated SWI/SNF complex reveals distinct roles for the BAP and PBAP complexes in post-mitotic memory forming neurons of the Drosophila mushroom body

2018 ◽  
Author(s):  
Melissa C. Chubak ◽  
Max H. Stone ◽  
Nicholas Raun ◽  
Shelby L. Rice ◽  
Mohammed Sarikahya ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mushroom Body ◽  
Functional Characterization ◽  
Long Term Memory ◽  
Term Memory ◽  
Functional Understanding ◽  
Short And Long Term ◽  
Cellular Components

AbstractTechnology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders like intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodeling complex is one of the most overrepresented cellular components disrupted in ID. We systematically investigated the role of individual subunits of this large protein complex in post-mitotic memory forming neurons of the Drosophila mushroom body (MB). Using this approach, we have identified novel differential roles for the two prominent conformations of the Drosophila SWI/SNF complex, known as BAP and PBAP. The PBAP conformation is required post-mitotically for remodeling of the MB γ neurons during morphogenesis and is essential for both short and long-term memory. In contrast, the BAP conformation appears to preferentially effect long-term memory and is associated with γ neuron survival. Our results suggest that different subunits of the SWI/SNF complex may influence learning and memory through diverse and distinct roles in regulating structural plasticity, survival, and functionality of post-mitotic neurons. This study provides novel insight into the neuronal function of individual SWI/SNF subunits and will serve as a basis for understanding SWI/SNF-mediated gene regulatory mechanisms in post-mitotic neurons.

scholarly journals Selectively increasing GHS-R1a expression in dCA1 excitatory/inhibitory neurons have opposite effects on memory encoding

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Nan Li ◽  
Na Li ◽  
Fenghua Xu ◽  
Ming Yu ◽  
Zichen Qiao ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Memory Performance ◽  
Critical Role ◽  
Inhibitory Neurons ◽  
Long Term Memory ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Term Memory ◽  
Selective Increase

Abstract Aim Growth hormone secretagogue receptor 1a (GHS-R1a) is widely distributed in brain including the hippocampus. Studies have demonstrated the critical role of hippocampal ghrelin/GHS-R1a signaling in synaptic physiology, memory and cognitive dysfunction associated with Alzheimer’s disease (AD). However, current reports are inconsistent, and the mechanism underlying memory modulation of GHS-R1a signaling is uncertain. In this study, we aim to investigate the direct impact of selective increase of GHS-R1a expression in dCA1 excitatory/inhibitory neurons on learning and memory. Methods Endogenous GHS-R1a distribution in dCA1 excitatory/inhibitory neurons was assessed by fluorescence in situ hybridization. Cre-dependent GHS-R1a overexpression in excitatory or inhibitory neurons was done by stereotaxic injection of aav-hSyn-DIO-hGhsr1a-2A-eGFP virus in dCA1 region of vGlut1-Cre or Dlx5/6-Cre mice respectively. Virus-mediated GHS-R1a upregulation in dCA1 neurons was confirmed by quantitative RT-PCR. Different behavioral paradigms were used to evaluate long-term memory performance. Results GHS-R1a is distributed both in dCA1 excitatory pyramidal neurons (αCaMKII+) and in inhibitory interneurons (GAD67+). Selective increase of GHS-R1a expression in dCA1 pyramidal neurons impaired spatial memory and object-place recognition memory. In contrast, selective increase of GHS-R1a expression in dCA1 interneurons enhanced long-term memory performance. Our findings reveal, for the first time, a neuronal type-specific role that hippocampal GHS-R1a signaling plays in regulating memory. Therefore, manipulating GHS-R1a expression/activity in different subpopulation of neurons may help to clarify current contradictory findings and to elucidate mechanism of memory control by ghrelin/GHS-R1a signaling, under both physiological and pathological conditions such as AD.

Sign in / Sign up

Export Citation Format

Share Document