-
Glia Aug 2022The entorhinal cortex-dentate gyrus circuit is centrally involved in memory processing conveying to the hippocampus spatial and nonspatial context information via,... (Review)
Review
The entorhinal cortex-dentate gyrus circuit is centrally involved in memory processing conveying to the hippocampus spatial and nonspatial context information via, respectively, medial and lateral perforant path (MPP and LPP) excitatory projections onto dentate granule cells (GCs). Here, we review work of several years from our group showing that astrocytes sense local synaptic transmission and exert in turn a presynaptic control at PP-GC synapses. Modulation of neurotransmitter release probability by astrocytes sets basal synaptic strength and dynamic range for long-term potentiation of PP-GC synapses. Intriguingly, this astrocyte control is circuit-specific, being present only at MPP-GC (not LPP-GC) synapses, which selectively express atypical presynaptic N-methyl-D-aspartate receptors (NMDAR) suitable to activation by astrocyte-released glutamate. Moreover, the astrocytic control is peculiarly dependent on the cytokine TNFα, which at constitutive levels acts as a gating factor for the astrocyte signaling. During inflammation/infection processes, increased levels of TNFα lead to uncontrolled astrocyte glutamate release, altered PP-GC circuit processing and, ultimately, impaired contextual memory performance. The TNFα-dependent pathological switch of the synaptic control from astrocytes and its deleterious consequences are observed in animal models of HIV brain infection and multiple sclerosis, conditions both known to cause cognitive disturbances in up to 50% of patients. The review also discusses open issues related to the identified astrocytic pathway: its role in contextual memory processing, potential damaging role in Alzheimer's disease, the existence of vesicular glutamate release from DG astrocytes, and the possible synaptic-like connectivity between astrocytic output sites and PP receptive sites.
Topics: Animals; Astrocytes; Cognition; Dentate Gyrus; Entorhinal Cortex; Glutamic Acid; Humans; Synapses; Tumor Necrosis Factor-alpha
PubMed: 34904753
DOI: 10.1002/glia.24128 -
European Journal of Neurology Sep 2023While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify...
INTRODUCTION
While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions.
METHODS
We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months.
RESULTS
Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group.
CONCLUSIONS
Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.
Topics: Humans; Huntington Disease; Hippocampus; Magnetic Resonance Imaging; Temporal Lobe; Atrophy
PubMed: 37306313
DOI: 10.1111/ene.15918 -
Cognitive Neurodynamics Apr 2022Understanding the pathogenesis of epilepsy including changes in synaptic pathways can improve our knowledge about epilepsy and development of new treatments. In this...
Understanding the pathogenesis of epilepsy including changes in synaptic pathways can improve our knowledge about epilepsy and development of new treatments. In this regard, data-driven models such as artificial neural networks, which are able to capture the effects of synaptic plasticity, can play an important role. This paper proposes long short term memory (LSTM) as the ideal architecture for modeling plasticity changes, and validates this proposal via experimental data. As a special class of recurrent neural networks (RNNs), LSTM is able to track information through time and control its flow via several gating mechanisms, which allow for maintaining the relevant and forgetting the irrelevant information. In our experiments, potentiation and depotentiation of motor circuit and perforant pathway as two forms of plasticity were respectively induced by kindled and kindled + transcranial magnetic stimulation of animal groups. In kindling, both procedure duration and gradual synaptic changes play critical roles. The stimulation of both groups continued for six days. Both after-discharge (AD) and seizure behavior as two biologically measurable effects of plasticity were recorded immediately post each stimulation. Three classes of artificial neural networks-LSTM, RNN, and feedforward neural network (FFNN)-were trained to predict AD and seizure behavior as indicators of plasticity during these six days. Results obtained from the collected data confirm the superiority of LSTM. For seizure behavior, the prediction accuracies achieved by these three models were 0.91 ± 0.01, 0.77 ± 0.02, and 0.59 ± 0.02%, respectively, and for AD, the prediction accuracies were 0.82 ± 0.01, 0.74 ± 0.08 and 0.42 ± 0.1, respectively.
PubMed: 35401870
DOI: 10.1007/s11571-021-09698-7 -
International Journal of Molecular... Nov 2017The basal levels of extracellular Zn are in the range of low nanomolar concentrations and less attention has been paid to Zn, compared to Ca, for synaptic activity.... (Review)
Review
The basal levels of extracellular Zn are in the range of low nanomolar concentrations and less attention has been paid to Zn, compared to Ca, for synaptic activity. However, extracellular Zn is necessary for synaptic activity. The basal levels of extracellular zinc are age-dependently increased in the rat hippocampus, implying that the basal levels of extracellular Zn are also increased age-dependently and that extracellular Zn dynamics are linked with age-related cognitive function and dysfunction. In the hippocampus, the influx of extracellular Zn into postsynaptic neurons, which is often linked with Zn release from neuron terminals, is critical for cognitive activity via long-term potentiation (LTP). In contrast, the excess influx of extracellular Zn into postsynaptic neurons induces cognitive decline. Interestingly, the excess influx of extracellular Zn more readily occurs in aged dentate granule cells and intracellular Zn-buffering, which is assessed with ZnAF-2DA, is weakened in the aged dentate granule cells. Characteristics (easiness) of extracellular Zn influx seem to be linked with the weakened intracellular Zn-buffering in the aged dentate gyrus. This paper deals with the impact of synaptic Zn signaling on cognition and its decline in comparison with synaptic Ca signaling.
Topics: Animals; Brain; Cognition; Cognition Disorders; Humans; Models, Neurological; Synapses; Zinc
PubMed: 29135924
DOI: 10.3390/ijms18112411 -
The Journal of Neuroscience : the... Jul 2023The perforant path provides the primary cortical excitatory input to the hippocampus. Because of its important role in information processing and coding, entorhinal...
The perforant path provides the primary cortical excitatory input to the hippocampus. Because of its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells remains to be characterized. Here, we have used mouse organotypic entorhino-hippocampal tissue cultures of either sex, in which the entorhinal cortex (EC) to dentate granule cell (GC; EC-GC) projection is present, and EC-GC pairs can be studied using whole-cell patch-clamp recordings. By using cultures of wild-type mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared, and differences in short-term plasticity were identified. As the perforant path is severely affected in Alzheimer's disease, we used tissue cultures of amyloid precursor protein (APP)-deficient mice to examine the role of APP at this synapse. APP deficiency altered excitatory neurotransmission at medial perforant path synapses, which was accompanied by transcriptomic and ultrastructural changes. Moreover, presynaptic but not postsynaptic APP deletion through the local injection of Cre-expressing adeno-associated viruses in conditional tissue cultures increased the neurotransmission efficacy at perforant path synapses. In summary, these data suggest a physiological role for presynaptic APP at medial perforant path synapses that may be adversely affected under altered APP processing conditions. The hippocampus receives input from the entorhinal cortex via the perforant path. These projections to hippocampal dentate granule cells are of utmost importance for learning and memory formation. Although there is detailed knowledge about perforant path projections, the functional synaptic properties at the level of individual connected pairs of neurons are not well understood. In this study, we investigated the role of APP in mediating functional properties and transmission rules in individually connected neurons using paired whole-cell patch-clamp recordings and genetic tools in organotypic tissue cultures. Our results show that presynaptic APP expression limits excitatory neurotransmission via the perforant path, which could be compromised in pathologic conditions such as Alzheimer's disease.
Topics: Mice; Animals; Perforant Pathway; Amyloid beta-Protein Precursor; Alzheimer Disease; Dentate Gyrus; Synaptic Transmission; Synapses
PubMed: 37369586
DOI: 10.1523/JNEUROSCI.1824-22.2023 -
Cells Jan 2022Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to...
Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3-CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212 mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3-CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212 mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212 mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.
Topics: Acetylcholinesterase; Aging; Animals; Cyclic AMP Response Element-Binding Protein; Dentate Gyrus; Gene Expression Regulation; Hippocampus; Long-Term Potentiation; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Neuronal Plasticity; Nicotine; Phosphorylation; Synaptic Transmission; Mice
PubMed: 35053378
DOI: 10.3390/cells11020261 -
Alzheimer's Research & Therapy Apr 2020Amyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain...
BACKGROUND
Amyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.
METHODS
To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).
RESULTS
It is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.
CONCLUSIONS
Our findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cognition; Disease Models, Animal; HEK293 Cells; Humans; Mice; Mice, Transgenic; Nogo Receptors; Perforant Pathway; Presenilin-1
PubMed: 32331528
DOI: 10.1186/s13195-020-00616-3 -
Aging Mar 2023Neuronal loss is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD causes the death of neurons point towards...
Neuronal loss is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD causes the death of neurons point towards protection of neuronal morphology and function as important therapeutic strategies. The perforant path projections from the entorhinal cortex to the dentate gyrus is the most vulnerable circuit with respect to AD. It's known that the perforant path is a very important structure for synaptic plasticity and cognitive functions. NgR (Nogo receptor) is not only involved in limiting injury-induced axonal growth but also in pathological features of AD. So, the mechanism of how NgR affects the perforant path needs further investigation. In this study, the effect of NgR in the perforant path on the neuronal morphology and function in APP/PS1 transgenic mice was studied. The results showed that downregulation of NgR in perforant path ameliorate the damaged morphology and decreased number of neurons in APP/PS1 mice. Concurrently, NgR knockdown enhanced dendritic complexity and increased postsynaptic protein density in APP/PS1 mice. Furthermore, the RT-PCR results indicated that there is downregulation of M1 phenotypes of microglial gene expression in the hippocampus of TG-shNgR mice. Our study suggests that NgR plays a critical role in microglial phenotype polarization, which might account for the NgR knockdown in the perforant path initiated a decrease in neuronal death and improved synaptic function. Our study provided a better understanding of the perforant path and the role of NgR in AD pathogenesis, thus offering the potential application of hippocampal neurons in treatment of AD.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Protein Precursor; Disease Models, Animal; Hippocampus; Mice, Transgenic; Neurons; Perforant Pathway; Nogo Receptor 1
PubMed: 36961417
DOI: 10.18632/aging.204605 -
Behavioural Brain Research May 2015Research into object recognition memory has been galvanised by the introduction of spontaneous preference tests for rodents. The standard task, however, contains a... (Review)
Review
Research into object recognition memory has been galvanised by the introduction of spontaneous preference tests for rodents. The standard task, however, contains a number of inherent shortcomings that reduce its power. Particular issues include the problem that individual trials are time consuming, so limiting the total number of trials in any condition. In addition, the spontaneous nature of the behaviour and the variability between test objects add unwanted noise. To combat these issues, the 'bow-tie maze' was introduced. Although still based on the spontaneous preference of novel over familiar stimuli, the ability to give multiple trials within a session without handling the rodents, as well as using the same objects as both novel and familiar samples on different trials, overcomes key limitations in the standard task. Giving multiple trials within a single session also creates new opportunities for functional imaging of object recognition memory. A series of studies are described that examine the expression of the immediate-early gene, c-fos. Object recognition memory is associated with increases in perirhinal cortex and area Te2 c-fos activity. When rats explore novel objects the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to the dentate gyrus and CA3, is engaged. In contrast, when familiar objects are explored the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to CA1, takes precedence. The switch to the perforant pathway (novel stimuli) from the temporoammonic pathway (familiar stimuli) may assist the enhanced associative learning promoted by novel stimuli.
Topics: Animals; Hippocampus; Neural Pathways; Neuropsychological Tests; Proto-Oncogene Proteins c-fos; Recognition, Psychology; Rodentia
PubMed: 25106740
DOI: 10.1016/j.bbr.2014.07.049