International Journal of Molecular Sciences

Research

19 pages, 3236 KiB

Open AccessArticle

Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APP_swe Alzheimer’s Disease Mouse Model

by Marta Zamarbide, Eva Martinez-Pinilla, Francisco Gil-Bea, Masashi Yanagisawa, Rafael Franco and Alberto Perez-Mediavilla

Int. J. Mol. Sci. 2022, 23(7), 3533; https://doi.org/10.3390/ijms23073533 - 24 Mar 2022

Cited by 4 | Viewed by 3052

Abstract

The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate [...] Read more.

The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APP_swe mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R^−/−/APP_swe, to perform cognition studies and to assess, by immunoblotting Aβ and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R^−/−/APP_swe mice do not have the characteristic memory impairment of 12-month-old APP_swe mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer’s disease (AD)-related features, such as amyloid beta (Aβ) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3β and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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16 pages, 4228 KiB

Open AccessArticle

Changes in Metabotropic Glutamate Receptor Gene Expression in Rat Brain in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy

by Anna A. Kovalenko, Maria V. Zakharova, Alexander P. Schwarz, Alexandra V. Dyomina, Olga E. Zubareva and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2022, 23(5), 2752; https://doi.org/10.3390/ijms23052752 - 2 Mar 2022

Cited by 6 | Viewed by 2755

Abstract

Preventing epileptogenesis in people at risk is an unmet medical need. Metabotropic glutamate receptors (mGluRs) are promising targets for such therapy. However, drugs acting on mGluRs are not used in the clinic due to limited knowledge of the involvement of mGluRs in epileptogenesis. [...] Read more.

Preventing epileptogenesis in people at risk is an unmet medical need. Metabotropic glutamate receptors (mGluRs) are promising targets for such therapy. However, drugs acting on mGluRs are not used in the clinic due to limited knowledge of the involvement of mGluRs in epileptogenesis. This study aimed to analyze the changes in gene expression of mGluR subtypes (1–5, 7, 8) in various rat brain regions in the latent and chronic phases of a lithium–pilocarpine model of epilepsy. For this study, multiplex test systems were selected and optimized to analyze mGluR gene expression using RT-qPCR. Region- and phase-specific changes in expression were revealed. During the latent phase, mGluR5 mRNA levels were increased in the dorsal and ventral hippocampus, and expression of group III genes was decreased in the hippocampus and temporal cortex, which could contribute to epileptogenesis. Most of the changes in expression detected in the latent stage were absent in the chronic stage, but mGluR8 mRNA production remained reduced in the hippocampus. Moreover, we found that gene expression of group II mGluRs was altered only in the chronic phase. The study deepened our understanding of the mechanisms of epileptogenesis and suggested that agonists of group III mGluRs are the most promising targets for preventing epilepsy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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18 pages, 4777 KiB

Open AccessArticle

Adenosine Kinase Isoforms in the Developing Rat Hippocampus after LiCl/Pilocarpine Status Epilepticus

by Petr Fábera, Libor Uttl, Hana Kubová, Grygoriy Tsenov and Pavel Mareš

Int. J. Mol. Sci. 2022, 23(5), 2510; https://doi.org/10.3390/ijms23052510 - 24 Feb 2022

Cited by 2 | Viewed by 2068

Abstract

LiCl/pilocarpine status epilepticus (SE) induced in immature rats leads, after a latent period, to hippocampal hyperexcitability. The excitability may be influenced by adenosine, which exhibits anticonvulsant activity. The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms—ADK-L and ADK-S. [...] Read more.

LiCl/pilocarpine status epilepticus (SE) induced in immature rats leads, after a latent period, to hippocampal hyperexcitability. The excitability may be influenced by adenosine, which exhibits anticonvulsant activity. The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms—ADK-L and ADK-S. The main goal of the study is to elucidate the changes in ADK isoform expression after LiCl/pilocarpine SE and whether potential changes, as well as inhibition of ADK by 5-iodotubercidin (5-ITU), may contribute to changes in hippocampal excitability during brain development. LiCl/pilocarpine SE was elicited in 12-day-old rats. Hippocampal excitability in immature rats was studied by the model of hippocampal afterdischarges (ADs), in which we demonstrated the potential inhibitory effect of 5-ITU. ADs demonstrated significantly decreased hippocampal excitability 3 days after SE induction, whereas significant hyperexcitability after 20 days compared to controls was shown. 5-ITU administration showed its inhibitory effect on the ADs in 32-day-old SE rats compared to SE rats without 5-ITU. Moreover, both ADK isoforms were examined in the immature rat hippocampus. The ADK-L isoform demonstrated significantly decreased expression in 12-day-old SE rats compared to the appropriate naïve rats, whereas increased ADK-S isoform expression was revealed. A decreasing ADK-L/-S ratio showed the declining dominance of ADK-L isoform during early brain development. LiCl/pilocarpine SE increased the excitability of the hippocampus 20 days after SE induction. The ADK inhibitor 5-ITU exhibited anticonvulsant activity at the same age. Age-related differences in hippocampal excitability after SE might correspond to the development of ADK isoform levels in the hippocampus. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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22 pages, 2015 KiB

Open AccessArticle

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

by Tatyana Strekalova, Dmitrii Pavlov, Alexander Trofimov, Daniel C. Anthony, Andrei Svistunov, Andrey Proshin, Aleksei Umriukhin, Alexei Lyundup, Klaus-Peter Lesch and Raymond Cespuglio

Int. J. Mol. Sci. 2022, 23(4), 2061; https://doi.org/10.3390/ijms23042061 - 13 Feb 2022

Cited by 15 | Viewed by 4013

Abstract

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all [...] Read more.

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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20 pages, 7623 KiB

Open AccessArticle

Changes in Glial Support of the Hippocampus during the Development of an Alzheimer’s Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1

by Ekaterina A. Rudnitskaya, Alena O. Burnyasheva, Tatiana A. Kozlova, Daniil A. Peunov, Nataliya G. Kolosova and Natalia A. Stefanova

Int. J. Mol. Sci. 2022, 23(3), 1134; https://doi.org/10.3390/ijms23031134 - 20 Jan 2022

Cited by 11 | Viewed by 3342

Abstract

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer’s disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics [...] Read more.

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer’s disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, and Wistar rats (parental normal strain, control), we investigated hippocampal neurogenesis and glial changes during AD-like pathology. Using immunohistochemistry, we showed that the early stage of the pathology is accompanied by a lower intensity of neurogenesis and decreased astrocyte density in the dentate gyrus. The progressive stage is concurrent with reactive astrogliosis and microglia activation, as confirmed by increased cell densities and by the acquisition of cell-specific gene expression profiles, according to transcriptome sequencing data. Besides, here, we continued to analyze the anti-AD effects of prolonged supplementation with mitochondria-targeted antioxidant SkQ1. The antioxidant did not affect neurogenesis, partly normalized the gene expression profile of astrocytes and microglia, and shifted the resting/activated microglia ratio toward a decrease in the activated-cell density. In summary, both astrocytes and microglia are more vulnerable to AD-associated neurodegeneration in the CA3 area than in other hippocampal areas; SkQ1 had an anti-inflammatory effect and is a promising modality for AD prevention and treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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14 pages, 1288 KiB

Open AccessArticle

A Comparative Study of Koizumi and Longa Methods of Intraluminal Filament Middle Cerebral Artery Occlusion in Rats: Early Corticosterone and Inflammatory Response in the Hippocampus and Frontal Cortex

by Mikhail V. Onufriev, Yulia V. Moiseeva, Marina Y. Zhanina, Natalia A. Lazareva and Natalia V. Gulyaeva

Int. J. Mol. Sci. 2021, 22(24), 13544; https://doi.org/10.3390/ijms222413544 - 17 Dec 2021

Cited by 18 | Viewed by 3394

Abstract

Two classical surgical approaches for intraluminal filament middle cerebral artery occlusion (MCAO), the Longa et al. (LM) and Koizumi et al. methods (KM), are used as alternatives in preclinical studies to induce stroke in rodents. Comparisons of these MCAO models in mice showed [...] Read more.

Two classical surgical approaches for intraluminal filament middle cerebral artery occlusion (MCAO), the Longa et al. (LM) and Koizumi et al. methods (KM), are used as alternatives in preclinical studies to induce stroke in rodents. Comparisons of these MCAO models in mice showed critical differences between them along with similarities (Smith et al. 2015; Morris et al. 2016). In this study, a direct comparison of MCAO-KM and MCAO-LM in rats was performed. Three days after MCAO, infarct volume, mortality rate, neurological deficit, and weight loss were similar in these models. MCAO-LM rats showed an increase in ACTH levels, while MCAO-KM rats demonstrated elevated corticosterone and interleukin-1β in blood serum. Corticosterone accumulation was detected in the frontal cortex (FC) and the hippocampus of the MCAO-KM group. IL1β beta increased in the ipsilateral hippocampus in the MCAO-KM group and decreased in the contralateral FC of MCAO-LM rats. Differences revealed between MCAO-KM and MCAO-LM suggest that corticosterone and interleukin-1β release as well as hippocampal accumulation is more expressed in MCAO-KM rats, predisposing them to corticosterone-dependent distant neuroinflammatory hippocampal damage. The differences between two models, particularly, malfunction of the hypothalamic–pituitary–adrenal axis, should be considered in the interpretation, comparison, and translation of pre-clinical experimental results. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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14 pages, 3383 KiB

Open AccessArticle

Role of L-Type Voltage-Gated Calcium Channels in Epileptiform Activity of Neurons

by Denis P. Laryushkin, Sergei A. Maiorov, Valery P. Zinchenko, Sergei G. Gaidin and Artem M. Kosenkov

Int. J. Mol. Sci. 2021, 22(19), 10342; https://doi.org/10.3390/ijms221910342 - 25 Sep 2021

Cited by 15 | Viewed by 3364

Abstract

Epileptic discharges manifest in individual neurons as abnormal membrane potential fluctuations called paroxysmal depolarization shift (PDS). PDSs can combine into clusters that are accompanied by synchronous oscillations of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in neurons. Here, we investigate [...] Read more.

Epileptic discharges manifest in individual neurons as abnormal membrane potential fluctuations called paroxysmal depolarization shift (PDS). PDSs can combine into clusters that are accompanied by synchronous oscillations of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in neurons. Here, we investigate the contribution of L-type voltage-gated calcium channels (VGCC) to epileptiform activity induced in cultured hippocampal neurons by GABA(A)R antagonist, bicuculline. Using KCl-induced depolarization, we determined the optimal effective doses of the blockers. Dihydropyridines (nifedipine and isradipine) at concentrations ≤ 10 μM demonstrate greater selectivity than the blockers from other groups (phenylalkylamines and benzothiazepines). However, high doses of dihydropyridines evoke an irreversible increase in [Ca²⁺]_i in neurons and astrocytes. In turn, verapamil and diltiazem selectively block L-type VGCC in the range of 1–10 μM, whereas high doses of these drugs block other types of VGCC. We show that L-type VGCC blockade decreases the half-width and amplitude of bicuculline-induced [Ca²⁺]_i oscillations. We also observe a decrease in the number of PDSs in a cluster and cluster duration. However, the pattern of individual PDSs and the frequency of the cluster occurrence change insignificantly. Thus, our results demonstrate that L-type VGCC contributes to maintaining the required [Ca²⁺]_i level during oscillations, which appears to determine the number of PDSs in the cluster. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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17 pages, 3886 KiB

Open AccessArticle

Ceftriaxone Treatment Weakens Long-Term Synaptic Potentiation in the Hippocampus of Young Rats

by Tatyana Y. Postnikova, Sergey L. Malkin, Maria V. Zakharova, Ilya V. Smolensky, Olga E. Zubareva and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2021, 22(16), 8417; https://doi.org/10.3390/ijms22168417 - 5 Aug 2021

Cited by 5 | Viewed by 2579

Abstract

Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of [...] Read more.

Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of ceftriaxone (CTX), an enhancer of glutamate transporter 1 expression, treatment on long-term synaptic potentiation (LTP) in the hippocampus of young rats. In this study, 5-day administration of CTX (200 mg/kg) significantly weakened LTP in CA3-CA1 synapses. As shown by electrophysiological recordings, LTP attenuation was associated with weakening of N-Methyl-D-aspartate receptor (NMDAR)-dependent signaling in synapses. However, PCR analysis did not show downregulation of NMDAR subunits or changes in the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. We assume that extracellular burst stimulation activates fewer synapses in CTX-treated animals because increased glutamate reuptake results in reduced spillover, and neighboring synapses do not participate in neurotransmission. Attenuation of LTP was not accompanied by noticeable behavioral changes in the CTX group, with no behavioral abnormalities observed in the open field test or Morris water maze test. Thus, our experiments show that increased glutamate clearance can impair long-term synaptic plasticity and that this phenomenon can be considered a potential side effect of CTX treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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Review

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15 pages, 1544 KiB

Open AccessReview

An Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory

by Sydney Weber Boutros, Vivek K. Unni and Jacob Raber

Int. J. Mol. Sci. 2022, 23(15), 8352; https://doi.org/10.3390/ijms23158352 - 28 Jul 2022

Cited by 17 | Viewed by 3683

Abstract

DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients [...] Read more.

DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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30 pages, 1574 KiB

Open AccessReview

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

by David Wegrzyn, Georg Juckel and Andreas Faissner

Int. J. Mol. Sci. 2022, 23(10), 5482; https://doi.org/10.3390/ijms23105482 - 13 May 2022

Cited by 27 | Viewed by 6381

Abstract

Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive [...] Read more.

Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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17 pages, 787 KiB

Open AccessReview

Early Life Events and Maturation of the Dentate Gyrus: Implications for Neurons and Glial Cells

by Viktor Aniol, Anna Manolova and Natalia Gulyaeva

Int. J. Mol. Sci. 2022, 23(8), 4261; https://doi.org/10.3390/ijms23084261 - 12 Apr 2022

Cited by 13 | Viewed by 3788

Abstract

The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. [...] Read more.

The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. Early life stress may modify maturation of the DG and induce lifelong alterations in its structure and functioning, underlying brain pathologies in adults. In this paper, maturation of neurons and glial cells (microglia and astrocytes) and the effects of early life events on maturation processes in the DG have been comprehensively reviewed. Early postnatal interventions affecting the DG eventually result in an altered number of granule neurons in the DG, ectopic location of neurons and changes in adult neurogenesis. Adverse events in early life provoke proinflammatory changes in hippocampal glia at cellular and molecular levels immediately after stress exposure. Later, the cellular changes may disappear, though alterations in gene expression pattern persist. Additional stressful events later in life contribute to manifestation of glial changes and behavioral deficits. Alterations in the maturation of neuronal and glial cells induced by early life stress are interdependent and influence the development of neural nets, thus predisposing the brain to the development of cognitive and psychiatric disorders. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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22 pages, 2277 KiB

Open AccessReview

A New Player in the Hippocampus: A Review on VGLUT3+ Neurons and Their Role in the Regulation of Hippocampal Activity and Behaviour

by Csilla Lea Fazekas, Adrienn Szabó, Bibiána Török, Krisztina Bánrévi, Pedro Correia, Tiago Chaves, Stéphanie Daumas and Dóra Zelena

Int. J. Mol. Sci. 2022, 23(2), 790; https://doi.org/10.3390/ijms23020790 - 12 Jan 2022

Cited by 3 | Viewed by 4644

Abstract

Glutamate is the most abundant excitatory amino acid in the central nervous system. Neurons using glutamate as a neurotransmitter can be characterised by vesicular glutamate transporters (VGLUTs). Among the three subtypes, VGLUT3 is unique, co-localising with other “classical” neurotransmitters, such as the inhibitory [...] Read more.

Glutamate is the most abundant excitatory amino acid in the central nervous system. Neurons using glutamate as a neurotransmitter can be characterised by vesicular glutamate transporters (VGLUTs). Among the three subtypes, VGLUT3 is unique, co-localising with other “classical” neurotransmitters, such as the inhibitory GABA. Glutamate, manipulated by VGLUT3, can modulate the packaging as well as the release of other neurotransmitters and serve as a retrograde signal through its release from the somata and dendrites. Its contribution to sensory processes (including seeing, hearing, and mechanosensation) is well characterised. However, its involvement in learning and memory can only be assumed based on its prominent hippocampal presence. Although VGLUT3-expressing neurons are detectable in the hippocampus, most of the hippocampal VGLUT3 positivity can be found on nerve terminals, presumably coming from the median raphe. This hippocampal glutamatergic network plays a pivotal role in several important processes (e.g., learning and memory, emotions, epilepsy, cardiovascular regulation). Indirect information from anatomical studies and KO mice strains suggests the contribution of local VGLUT3-positive hippocampal neurons as well as afferentations in these events. However, further studies making use of more specific tools (e.g., Cre-mice, opto- and chemogenetics) are needed to confirm these assumptions. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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15 pages, 1248 KiB

Open AccessReview

Post-Ischemic Neurodegeneration of the Hippocampus Resembling Alzheimer’s Disease Proteinopathy

by Ryszard Pluta, Sławomir Januszewski and Stanisław J. Czuczwar

Int. J. Mol. Sci. 2022, 23(1), 306; https://doi.org/10.3390/ijms23010306 - 28 Dec 2021

Cited by 4 | Viewed by 2763

Abstract

In this review, we summarize, inter alia, the protein and gene changes associated with Alzheimer’s disease and their role in post-ischemic hippocampal neurodegeneration. In the hippocampus, studies have revealed dysregulation of the genes for the amyloid protein precursor metabolism and tau protein that [...] Read more.

In this review, we summarize, inter alia, the protein and gene changes associated with Alzheimer’s disease and their role in post-ischemic hippocampal neurodegeneration. In the hippocampus, studies have revealed dysregulation of the genes for the amyloid protein precursor metabolism and tau protein that is identical in nature to Alzheimer’s disease. Data indicate that amyloid and tau protein, derived from brain tissue and blood due to increased permeability of the blood–brain barrier after ischemia, play a key role in post-ischemic neurodegeneration of the hippocampus, with concomitant development of full-blown dementia. Thus, the knowledge of new neurodegenerative mechanisms that cause neurodegeneration of the hippocampus after ischemia, resembling Alzheimer’s disease proteinopathy, will provide the most important therapeutic development goals to date. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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12 pages, 923 KiB

Open AccessReview

Significance of GABA_A Receptor for Cognitive Function and Hippocampal Pathology

by Yuya Sakimoto, Paw Min-Thein Oo, Makoto Goshima, Itsuki Kanehisa, Yutaro Tsukada and Dai Mitsushima

Int. J. Mol. Sci. 2021, 22(22), 12456; https://doi.org/10.3390/ijms222212456 - 18 Nov 2021

Cited by 28 | Viewed by 5502

Abstract

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or [...] Read more.

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABA_A (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABA_A receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABA_A receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABA_A receptor trafficking, synaptic E/I imbalance and neuronal excitability. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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17 pages, 1559 KiB

Open AccessReview

Ferroptosis Mechanisms Involved in Hippocampal-Related Diseases

by Xintong Wang, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen

Int. J. Mol. Sci. 2021, 22(18), 9902; https://doi.org/10.3390/ijms22189902 - 14 Sep 2021

Cited by 26 | Viewed by 4265

Abstract

Ferroptosis is a newly recognized type of cell death that is different from traditional forms of cell death, such as apoptosis, autophagy, and necrosis. It is caused by the accumulation of intracellular iron, promoting lipid peroxidation and leading to cell death. Iron is [...] Read more.

Ferroptosis is a newly recognized type of cell death that is different from traditional forms of cell death, such as apoptosis, autophagy, and necrosis. It is caused by the accumulation of intracellular iron, promoting lipid peroxidation and leading to cell death. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. An increased concentration of iron in the central nervous system has been associated with oxidative stress, lipid peroxidation of proteins, and cell death. The hippocampus is an important brain region for learning, memory, and emotional responses, and is also a sensitive part of the brain to the dysfunctional homeostasis of transition metals. Damage of hippocampal structure and function are intimately involved in the pathogenic mechanisms underlying neurodegenerative diseases. Currently, ferroptosis is playing an increasingly important role in treatment areas of central nervous system diseases. Thus, we provide an overview of ferroptosis regulatory mechanisms, such as lipid metabolism, glutathione metabolism, and iron metabolism in this review. We also highlight the role of ferroptosis in hippocampal-related diseases and investigate a theoretical basis for further research on the role of ferroptosis in nervous system disease treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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Other

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13 pages, 1267 KiB

Open AccessHypothesis

Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer’s Disease

by Krisztián A. Kovács

Int. J. Mol. Sci. 2022, 23(1), 462; https://doi.org/10.3390/ijms23010462 - 31 Dec 2021

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Abstract

The medial temporal lobe memory system has long been identified as the brain region showing the first histopathological changes in early Alzheimer’s disease (AD), and the functional decline observed in patients also points to a loss of function in this brain area. Nonetheless, [...] Read more.

The medial temporal lobe memory system has long been identified as the brain region showing the first histopathological changes in early Alzheimer’s disease (AD), and the functional decline observed in patients also points to a loss of function in this brain area. Nonetheless, the exact identity of the neurons and networks that undergo deterioration has not been determined so far. A recent study has identified the entorhinal and hippocampal neural circuits responsible for encoding new episodic memories. Using this novel model we describe the elements of the episodic memory network that are especially vulnerable in early AD. We provide a hypothesis of how reduced reelin signaling within such a network can promote AD-related changes. Establishing novel associations and creating a temporal structure for new episodic memories are both affected in AD. Here, we furnish a reasonable explanation for both of these previous observations. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point)

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Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point

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