Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

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Inducible molecular switches for the study of long-term potentiation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2002.1245 ◽

2003 ◽

Vol 358 (1432) ◽

pp. 797-804 ◽

Cited By ~ 19

Author(s):

Gaël Hédou ◽

Isabelle M. Mansuy

Keyword(s):

Molecular Mechanisms ◽

Long Term Potentiation ◽

Knock Out ◽

Technical Developments ◽

Term Potentiation ◽

Dependent Protein ◽

Strength And Plasticity ◽

Regulated Gene Expression ◽

Molecular Bases

This article reviews technical and conceptual advances in unravelling the molecular bases of long-term potentiation (LTP), learning and memory using genetic approaches. We focus on studies aimed at testing a model suggesting that protein kinases and protein phosphatases balance each other to control synaptic strength and plasticity. We describe how gene ‘knock-out’ technology was initially exploited to disrupt the Ca 2+ /calmodulin-dependent protein kinase II α (CaMKII α ) gene and how refined knock-in techniques later allowed an analysis of the role of distinct phosphorylation sites in CaMKII. Further to gene recombination, regulated gene expression using the tetracycline-controlled transactivator and reverse tetracycline-controlled transactivator systems, a powerful new means for modulating the activity of specific molecules, has been applied to CaMKII α and the opposing protein phosphatase calcineurin. Together with electro-physiological and behavioural evaluation of the engineered mutant animals, these genetic methodologies have helped gain insight into the molecular mechanisms of plasticity and memory. Further technical developments are, however, awaited for an even higher level of finesse.

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Kalirin, a Key Player in Synapse Formation, Is Implicated in Human Diseases

Neural Plasticity ◽

10.1155/2012/728161 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 35

Author(s):

Prashant Mandela ◽

Xin-Ming Ma

Keyword(s):

Learning And Memory ◽

Cortical Neurons ◽

Molecular Mechanisms ◽

Synapse Formation ◽

Pdz Domain ◽

Long Term Potentiation ◽

Human Diseases ◽

Binding Motif ◽

Spine Density ◽

Morphological Alterations

Synapse formation is considered to be crucial for learning and memory. Understanding the underlying molecular mechanisms of synapse formation is a key to understanding learning and memory. Kalirin-7, a major isoform of Kalirin in adult rodent brain, is an essential component of mature excitatory synapses. Kalirin-7 interacts with multiple PDZ-domain-containing proteins including PSD95, spinophilin, and GluR1 through its PDZ-binding motif. In cultured hippocampal/cortical neurons, overexpression of Kalirin-7 increases spine density and spine size whereas reduction of endogenous Kalirin-7 expression decreases synapse number, and spine density. In Kalirin-7 knockout mice, spine length, synapse number, and postsynaptic density (PSD) size are decreased in hippocampal CA1 pyramidal neurons; these morphological alterations are accompanied by a deficiency in long-term potentiation (LTP) and a decreased spontaneous excitatory postsynaptic current (sEPSC) frequency. Human Kalirin-7, also known as Duo or Huntingtin-associated protein-interacting protein (HAPIP), is equivalent to rat Kalirin-7. Recent studies show that Kalirin is relevant to many human diseases such as Huntington’s Disease, Alzheimer’s Disease, ischemic stroke, schizophrenia, depression, and cocaine addiction. This paper summarizes our recent understanding of Kalirin function.

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Multiple cannabinoid signaling cascades powerfully suppress recurrent excitation in the hippocampus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017590118 ◽

2021 ◽

Vol 118 (4) ◽

pp. e2017590118

Author(s):

Kyle R. Jensen ◽

Coralie Berthoux ◽

Kaoutsar Nasrallah ◽

Pablo E. Castillo

Keyword(s):

Cannabinoid Receptors ◽

Granule Cells ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Epileptic Activity ◽

Axon Terminals ◽

Excitatory Transmission ◽

Term Potentiation ◽

Dependent Learning

Recurrent excitatory neural networks are unstable. In the hippocampus, excitatory mossy cells (MCs) receive strong excitatory inputs from dentate granule cells (GCs) and project back onto the proximal dendrites of GCs. By targeting the ipsi- and contralateral dentate gyrus (DG) along the dorsoventral axis of the hippocampus, MCs form an extensive recurrent excitatory circuit (GC-MC-GC) whose dysregulation can promote epilepsy. We recently reported that a physiologically relevant pattern of MC activity induces a robust form of presynaptic long-term potentiation (LTP) of MC-GC transmission which enhances GC output. Left unchecked, this LTP may interfere with DG-dependent learning, like pattern separation—which relies on sparse GC firing—and may even facilitate epileptic activity. Intriguingly, MC axons display uniquely high expression levels of type-1 cannabinoid receptors (CB1Rs), but their role at MC-GC synapses is poorly understood. Using rodent hippocampal slices, we report that constitutively active CB1Rs, presumably via βγ subunits, selectively inhibited MC inputs onto GCs but not MC inputs onto inhibitory interneurons or CB1R-sensitive inhibitory inputs onto GCs. Tonic CB1R activity also inhibited LTP and GC output. Furthermore, brief endocannabinoid release from GCs dampened MC-GC LTP in two mechanistically distinct ways: during induction via βγ signaling and before induction via αi/o signaling in a form of presynaptic metaplasticity. Lastly, a single in vivo exposure to exogenous cannabinoids was sufficient to induce this presynaptic metaplasticity. By dampening excitatory transmission and plasticity, tonic and phasic CB1R activity at MC axon terminals may preserve the sparse nature of the DG and protect against runaway excitation.

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Long-Term Depression in Identified Stellate Neurons of Juvenile Rat Entorhinal Cortex

Journal of Neurophysiology ◽

10.1152/jn.01089.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 727-737 ◽

Cited By ~ 39

Author(s):

Pan-Yue Deng ◽

Saobo Lei

Keyword(s):

Entorhinal Cortex ◽

Molecular Mechanisms ◽

Granule Cells ◽

Long Term Potentiation ◽

Cellular Mechanism ◽

Perforant Path ◽

High Frequency Stimulation ◽

Cortical Input ◽

Frequency Stimulation

The entorhinal cortex (EC) serves as a gateway to the hippocampus and plays a pivotal role in memory processing in the brain. Superficial layers of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. Whereas the EC expresses long-term potentiation (LTP) and depression (LTD), the underlying cellular and molecular mechanisms have not been determined. Because the axons of the stellate neurons in layer II of the EC form the perforant path that innervates the dentate gyrus granule cells of the hippocampus, we studied the mechanisms underlying the long-term plasticity in identified stellate neurons. Application of high-frequency stimulation (100 Hz for 1 s, repeated 3 times at an interval of 10 s) or forskolin (50 μM) failed to induce significant changes in synaptic strength, whereas application of pairing (presynaptic stimulation at 0.33 Hz paired with postsynaptic depolarization from −60 to −10 mV for 5 min) or low-frequency stimulation (LFS, 1 Hz for 15 min) paradigm-induced LTD. Pairing- or LFS-induced LTDs were N-methyl-d-aspartate receptor-dependent and occluded each other suggesting that they have the similar cellular mechanism. Pairing-induced LTD required the activity of calcineurin and involved AMPA receptor endocytosis that required the function of ubiquitin–proteasome system. Our study provides a cellular mechanism that might in part explain the role of the EC in memory.

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Effects of aging on axon terminals in the dentate molecular layer

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128924 ◽

1987 ◽

Vol 45 ◽

pp. 928-929

Author(s):

K. Cullen-Dockstader ◽

E. Fifkova

Keyword(s):

Granule Cells ◽

Molecular Layer ◽

Age Groups ◽

Long Term Potentiation ◽

Male Rats ◽

Perforant Path ◽

Axon Terminals ◽

Fischer 344 ◽

Spatial Memory Deficit ◽

Effects Of Aging

Normal aging results in a pronounced spatial memory deficit associated with a rapid decay of long-term potentiation at the synapses between the perforant path and spines in the medial and distal thirds of the dentate molecular layer (DML), suggesting the alteration of synaptic transmission in the dentate fascia. While the number of dentate granule cells remains unchanged, and there are no obvious pathological changes in these cells associated with increasing age, the density of their axospinous contacts has been shown to decrease. There are indications that the presynaptic element is affected by senescence before the postsynaptic element, yet little attention has been given to the fine structure of the remaining axon terminals. Therefore, we studied the axon terminals of the perforant path in the DML across three age groups.5 Male rats (Fischer 344) of each age group (3, 24 and 30 months), were perfused through the aorta.

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Congenital hypothyroidism impairs spine growth of dentate granule cells by downregulation of CaMKIV

Cell Death Discovery ◽

10.1038/s41420-021-00530-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qingying Tang ◽

Shuxia Chen ◽

Hui Wu ◽

Honghua Song ◽

Yongjun Wang ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Granule Cells ◽

Spine Density ◽

Drug Induced ◽

Distinct Cell Type ◽

Cognitive Behaviors ◽

Dentate Granule Cells ◽

Rat Pups ◽

Cognitive Deficiency ◽

Underlying Mechanisms

AbstractCongenital hypothyroidism (CH), a common neonatal endocrine disorder, can result in cognitive deficits if delay in diagnose and treatment. Dentate gyrus (DG) is the severely affected subregion of the hippocampus by the CH, where the dentate granule cells (DGCs) reside in. However, how CH impairs the cognitive function via affecting DGCs and the underlying mechanisms are not fully elucidated. In the present study, the CH model of rat pups was successfully established, and the aberrant dendrite growth of the DGCs and the impaired cognitive behaviors were observed in the offspring. Transcriptome analysis of hippocampal tissues following rat CH successfully identified that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was the prominent regulator involved in mediating deficient growth of DGC dendrites. CaMKIV was shown to be dynamically regulated in the DG subregion of the rats following drug-induced CH. Interference of CaMKIV expression in the primary DGCs significantly reduced the spine density of dendrites, while addition of T3 to the primary DGCs isolated from CH pups could facilitate the spine growth of dendrites. Insights into relevant mechanisms revealed that CH-mediated CaMKIV deficiency resulted in the significant decrease of phosphorylated CREB in DGCs, in association with the abnormality of dendrites. Our results have provided a distinct cell type in hippocampus that is affected by CH, which would be beneficial for the treatment of CH-induced cognitive deficiency.

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Developmental up-regulation of NMDA receptors in the prefrontal cortex and hippocampus of mGlu5 receptor knock-out mice

Molecular Brain ◽

10.1186/s13041-021-00784-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tiziana Imbriglio ◽

Remy Verhaeghe ◽

Nico Antenucci ◽

Stefania Maccari ◽

Giuseppe Battaglia ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nmda Receptor ◽

Metabotropic Glutamate Receptors ◽

Adult Life ◽

Developmental Time ◽

Postnatal Life ◽

Developmental Studies ◽

Knock Out ◽

Nmda Receptor Subunits ◽

The Impact

AbstractmGlu5 metabotropic glutamate receptors are highly expressed and functional in the early postnatal life, and are known to positively modulate NMDA receptor function. Here, we examined the expression of NMDA receptor subunits and interneuron-related genes in the prefrontal cortex and hippocampus of mGlu5−/− mice and wild-type littermates at three developmental time points (PND9, − 21, and − 75). We were surprised to find that expression of all NMDA receptor subunits was greatly enhanced in mGlu5−/− mice at PND21. In contrast, at PND9, expression of the GluN2B subunit was enhanced, whereas expression of GluN2A and GluN2D subunits was reduced in both regions. These modifications were transient and disappeared in the adult life (PND75). Changes in the transcripts of interneuron-related genes (encoding parvalbumin, somatostatin, vasoactive intestinal peptide, reelin, and the two isoforms of glutamate decarboxylase) were also observed in mGlu5−/− mice across postnatal development. For example, the transcript encoding parvalbumin was up-regulated in the prefrontal cortex of mGlu5−/− mice at PND9 and PND21, whereas it was significantly reduced at PND75. These findings suggest that in mGlu5−/− mice a transient overexpression of NMDA receptor subunits may compensate for the lack of the NMDA receptor partner, mGlu5. Interestingly, in mGlu5−/− mice the behavioral response to the NMDA channel blocker, MK-801, was significantly increased at PND21, and largely reduced at PND75. The impact of adaptive changes in the expression of NMDA receptor subunits should be taken into account when mGlu5−/− mice are used for developmental studies.

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Deficiency of the onco-miRNA cluster, miR-106b∼25, causes oligozoospermia and the cooperative action of miR-106b∼25 and miR-17∼92 is required to maintain male fertility

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa027 ◽

2020 ◽

Vol 26 (6) ◽

pp. 389-401

Author(s):

Alicia Hurtado ◽

Rogelio Palomino ◽

Ina Georg ◽

Miguel Lao ◽

Francisca M Real ◽

...

Keyword(s):

Male Fertility ◽

Molecular Mechanisms ◽

Mirna Cluster ◽

Knock Out ◽

Cooperative Action ◽

Mouse Mutants ◽

New Genes ◽

Mirna Clusters ◽

Testicular Histology ◽

And Function

Abstract The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analyzed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92+/−; miR-106b∼25−/− double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well-known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.

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