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1.
Front Aging Neurosci ; 14: 914491, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35936771

RESUMEN

Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer's disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear. In this study, we used local injections of AAV virus containing a dominant-negative (DN) Rac1 under the control of CaMKIIα promoter and found that the reduction of Rac1 hyperactivity in ventral hippocampal excitatory neurons improves social recognition memory in APP/PS1 mice. Expression of DN Rac1 also improves long-term potentiation, a key synaptic mechanism for memory formation. Our results suggest that overactivation of Rac1 in hippocampal excitatory neurons contributes to social memory deficits in APP/PS1 mice and that manipulating Rac1 activity may provide a potential therapeutic strategy to treat social deficits in AD.

2.
Cells ; 10(8)2021 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-34440848

RESUMEN

Learning and memory require structural and functional modifications of synaptic connections, and synaptic deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 and LIMK2) are key regulators of the actin cytoskeleton by affecting the actin-binding protein, cofilin. In addition, LIMK1 is implicated in the regulation of gene expression by interacting with the cAMP-response element-binding protein. Accumulating evidence indicates that LIMKs are critically involved in brain function and dysfunction. In this paper, we will review studies on the roles and underlying mechanisms of LIMKs in the regulation of long-term potentiation (LTP) and depression (LTD), the most extensively studied forms of long-lasting synaptic plasticity widely regarded as cellular mechanisms underlying learning and memory. We will also discuss the involvement of LIMKs in the regulation of the dendritic spine, the structural basis of synaptic plasticity, and memory formation. Finally, we will discuss recent progress on investigations of LIMKs in neurological and mental disorders, including Alzheimer's, Parkinson's, Williams-Beuren syndrome, schizophrenia, and autism spectrum disorders.


Asunto(s)
Encefalopatías/patología , Quinasas Lim/metabolismo , Plasticidad Neuronal/fisiología , Animales , Encefalopatías/metabolismo , Humanos , Quinasas Lim/deficiencia , Quinasas Lim/genética , Memoria/fisiología , Transducción de Señal , Sinapsis/metabolismo
3.
Neuropharmacology ; 194: 108630, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34089730

RESUMEN

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the principal mediators of fast excitatory synaptic transmission and they are required for various forms of synaptic plasticity, including long-term potentiation (LTP) and depression (LTD), which are key mechanisms of learning and memory. AMPARs are tetrameric complexes assembled from four subunits (GluA1-4), however, the lack of subunit-specific pharmacological tools has made the assessment of individual subunits difficult. The application of genetic techniques, particularly gene targeting, allows for precise manipulation and dissection of each subunit in the regulation of neuronal function and behaviour. In this review, we summarize studies using various mouse models with genetically altered AMPARs and focus on their roles in basal synaptic transmission, LTP, and LTD at the hippocampal CA1 synapse. These studies provide strong evidence that there are multiple forms of LTP and LTD at this synapse which can be induced by various induction protocols, and they are differentially regulated by different AMPAR subunits and domains. We conclude that it is necessary to delineate the mechanism of each of these forms of plasticity and their contribution to memory and brain disorders.


Asunto(s)
Plasticidad Neuronal/genética , Receptores AMPA/genética , Receptores de Glutamato/genética , Animales , Animales Modificados Genéticamente , Marcación de Gen , Ácido Glutámico , Hipocampo , Aprendizaje , Ratones , Modelos Genéticos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico
4.
Brain Struct Funct ; 225(6): 1817-1838, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32535839

RESUMEN

The present study investigated the short-term and long-term synaptic plasticity of excitatory synapses formed by the nucleus reuniens (RE) and entorhinal cortex (EC) on the distal apical dendrites of CA1 pyramidal cells. RE-CA1 synapses are implicated in memory involving the hippocampus and medial prefrontal cortex. Current source density (CSD) analysis was used to identify excitatory and inhibitory currents following stimulation of RE or medial perforant path (MPP) in urethane-anesthetized mice in vivo. At the distal apical dendrites, RE evoked an initial excitatory sink followed by inhibitory sources at short (~ 30 ms) and long (150-200 ms) latencies, and often showing gamma (25-40 Hz) oscillations. Both RE-evoked and spontaneous gamma-frequency local field potentials displayed the same CSD depth profile. Paired-pulse facilitation (PPF) of the distal excitatory sink at 20-200 ms interpulse intervals was observed following RE stimulation, generally higher than that following MPP stimulation. Theta-frequency burst stimulation (TBS) of RE induced input-specific long-term potentiation (LTP) at the distal dendritic CA1 synapses, accompanied by reduction of PPF. After TBS of the MPP, the MPP-CA1 distal dendritic synapse could manifest LTP or long-term depression, but the non-tetanized RE-CA1 synapse was typically potentiated. Heterosynaptic potentiation of the RE to CA1 distal synapses may occur after repeated activity of EC afferents, or spread of MPP stimulus currents to coursing RE afferents. The results indicate a propensity of RE-CA1 distal excitatory synapses to show PPF, LTP and gamma oscillations, all of which may participate in memory processing by RE and EC.


Asunto(s)
Región CA1 Hipocampal/fisiología , Dendritas/fisiología , Corteza Entorrinal/fisiología , Potenciación a Largo Plazo , Núcleos Talámicos de la Línea Media/fisiología , Sinapsis/fisiología , Animales , Estimulación Eléctrica , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Células Piramidales/fisiología
5.
Hippocampus ; 30(6): 565-581, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31713968

RESUMEN

α-Thalassemia X-linked intellectual disability (ATR-X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2-type chromatin-remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX-cKO) causes deficits in long-term hippocampus-dependent spatial memory. Thus, we hypothesized that ATRX-cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane-anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired-pulse facilitation (PPF) at 50-ms interpulse interval, and by their long-term potentiation (LTP) induced by theta-frequency burst stimulation. Baseline single-pulse excitatory response at each synapse did not differ between ATRX-cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX-cKO mice. While basal dendritic LTP of the first-pulse excitatory response was not affected in ATRX-cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long-term spatial memory deficits in ATRX-cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR-X syndrome patients.


Asunto(s)
Hipocampo/metabolismo , Plasticidad Neuronal/fisiología , Prosencéfalo/metabolismo , Sinapsis/metabolismo , Proteína Nuclear Ligada al Cromosoma X/deficiencia , Animales , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/citología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Prosencéfalo/citología , Proteína Nuclear Ligada al Cromosoma X/genética
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