Consolidation and maintenance of Drosophila long-term memory require LIM homeodomain protein Apterous in distinct brain neurons

AbstractThe LIM-homeodomain (LIM-HD) transcription factor Apterous (Ap) and its cofactor Chip (Chi) form a complex that regulates various developmental events in Drosophila. Although Ap continues to be expressed in the adult brain, the functions of the centrally expressed Ap remain incompletely understood. Here, we show that Ap and Chi in the Drosophila memory center, the mushroom bodies (MBs), are indispensable for long-term memory (LTM) maintenance, whereas Ap in a subset of clock neurons [large ventral-lateral neurons (l-LNvs)] plays a crucial role in memory consolidation in a Chi-independent manner. Ex vivo imaging revealed that Ap, but not Chi, in l-LNvs is essential for the appropriate Cl− responses to GABA. Furthermore, knockdown of GABAA receptor in l-LNvs compensated for the impairment of memory consolidation in ap null mutant flies. Our results indicate that Drosophila Ap functions differently in l-LNvs and MBs, and it contributes to the consolidation and maintenance of LTM.

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Consolidation and maintenance of long-term memory involve dual functions of the developmental regulator Apterous in clock neurons and mushroom bodies in the Drosophila brain

PLoS Biology ◽

10.1371/journal.pbio.3001459 ◽

2021 ◽

Vol 19 (12) ◽

pp. e3001459

Author(s):

Show Inami ◽

Tomohito Sato ◽

Yuto Kurata ◽

Yuki Suzuki ◽

Toshihiro Kitamoto ◽

...

Keyword(s):

Memory Consolidation ◽

Ex Vivo ◽

Adult Brain ◽

Mushroom Bodies ◽

Long Term Memory ◽

Gamma Aminobutyric Acid ◽

Behavioral Arousal ◽

Term Memory ◽

Dual Functions

Memory is initially labile but can be consolidated into stable long-term memory (LTM) that is stored in the brain for extended periods. Despite recent progress, the molecular and cellular mechanisms underlying the intriguing neurobiological processes of LTM remain incompletely understood. Using the Drosophila courtship conditioning assay as a memory paradigm, here, we show that the LIM homeodomain (LIM-HD) transcription factor Apterous (Ap), which is known to regulate various developmental events, is required for both the consolidation and maintenance of LTM. Interestingly, Ap is involved in these 2 memory processes through distinct mechanisms in different neuronal subsets in the adult brain. Ap and its cofactor Chip (Chi) are indispensable for LTM maintenance in the Drosophila memory center, the mushroom bodies (MBs). On the other hand, Ap plays a crucial role in memory consolidation in a Chi-independent manner in pigment dispersing factor (Pdf)-containing large ventral–lateral clock neurons (l-LNvs) that modulate behavioral arousal and sleep. Since disrupted neurotransmission and electrical silencing in clock neurons impair memory consolidation, Ap is suggested to contribute to the stabilization of memory by ensuring the excitability of l-LNvs. Indeed, ex vivo imaging revealed that a reduced function of Ap, but not Chi, results in exaggerated Cl− responses to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in l-LNvs, indicating that wild-type (WT) Ap maintains high l-LNv excitability by suppressing the GABA response. Consistently, enhancing the excitability of l-LNvs by knocking down GABAA receptors compensates for the impaired memory consolidation in ap null mutants. Overall, our results revealed unique dual functions of the developmental regulator Ap for LTM consolidation in clock neurons and LTM maintenance in MBs.

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Notch signalling becomes transiently attenuated during long-term memory consolidation in adult Wistar rats

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2007.04.006 ◽

2007 ◽

Vol 88 (3) ◽

pp. 342-351 ◽

Cited By ~ 26

Author(s):

Lisa Conboy ◽

Claire M. Seymour ◽

Marco P. Monopoli ◽

Niamh C. O’Sullivan ◽

Keith J. Murphy ◽

...

Keyword(s):

Memory Consolidation ◽

Wistar Rats ◽

Notch Signalling ◽

Long Term Memory ◽

Term Memory

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Noradrenergic Control of Long-Term Memory Consolidation

Catecholamine Research - Advances in Behavioral Biology ◽

10.1007/978-1-4757-3538-3_84 ◽

2002 ◽

pp. 353-356

Author(s):

Kazuto Kobayashi ◽

Yasunobu Yasoshima

Keyword(s):

Memory Consolidation ◽

Long Term Memory ◽

Term Memory

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Memory Consolidation and the Distinction between Short-Term and Long-Term Memory

The Future of the Brain Sciences ◽

10.1007/978-1-4899-6323-9_35 ◽

1969 ◽

pp. 335-340

Author(s):

Samuel Bogoch

Keyword(s):

Memory Consolidation ◽

Long Term Memory ◽

Short Term ◽

Term Memory

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The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics

Journal of Neurophysiology ◽

10.1152/jn.00370.2019 ◽

2019 ◽

Vol 122 (3) ◽

pp. 1123-1135 ◽

Cited By ~ 1

Author(s):

C. J. Scavuzzo ◽

M. J. LeBlancq ◽

F. Nargang ◽

H. Lemieux ◽

T. J. Hamilton ◽

...

Keyword(s):

Protein Synthesis ◽

Mitochondrial Function ◽

Neural Activity ◽

Memory Consolidation ◽

Hippocampal Neurons ◽

Membrane Properties ◽

Long Term Memory ◽

Term Memory ◽

Cellular Energetics

The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary. NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.

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