Cell
MinireviewSynaptic plasticity in the hippocampus: LTP and LTD
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Cited by (565)
Aquaporin 4 beyond a water channel; participation in motor, sensory, cognitive and psychological performances, a comprehensive review
2023, Physiology and BehaviorAquaporin 4 (AQP4) is a protein highly expressed in the central nervous system (CNS) and peripheral nervous system (PNS) as well as various other organs, whose different sites of action indicate its importance in various functions. AQP4 has a variety of essential roles beyond water homeostasis. In this article, we have for the first time summarized different roles of AQP4 in motor and sensory functions, besides cognitive and psychological performances, and most importantly, possible physiological mechanisms by which AQP4 can exert its effects. Furthermore, we demonstrated that AQP4 participates in pathology of different neurological disorders, various effects depending on the disease type. Since neurological diseases involve a spectrum of dysfunctions and due to the difficulty of obtaining a treatment that can simultaneously affect these deficits, it is therefore suggested that future studies consider the role of this protein in different functional impairments related to neurological disorders simultaneously or separately by targeting AQP4 expression and/or polarity modulation.
Putative pathological mechanisms of late-life depression and Alzheimer's disease
2023, Brain ResearchAlzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by progressive impairment in cognition and memory. AD is accompanied by several neuropsychiatric symptoms, with depression being the most prominent. Although depression has long been known to be associated with AD, controversial findings from preclinical and clinical studies have obscured the precise nature of this association. However recent evidence suggests that depression could be a prodrome or harbinger of AD. Evidence indicates that the major central serotonergic nucleus–the dorsal raphe nucleus (DRN)–shows very early AD pathology: neurofibrillary tangles made of hyperphosphorylated tau protein and degenerated neurites. AD and depression share common pathophysiologies, including functional deficits of the serotonin (5-HT) system. 5-HT receptors have modulatory effects on the progression of AD pathology i.e., reduction in Aβ load, increased hyper-phosphorylation of tau, decreased oxidative stress etc. Moreover, preclinical models show a role for specific channelopathies that result in abnormal regional activational and neuroplasticity patterns. One of these concerns the pathological upregulation of the small conductance calcium-activated potassium (SK) channel in corticolimbic structure. This has also been observed in the DRN in both diseases. The SKC is a key regulator of cell excitability and long-term potentiation (LTP). SKC over-expression is positively correlated with aging and cognitive decline, and is evident in AD. Pharmacological blockade of SKCs has been reported to reverse symptoms of depression and AD. Thus, aberrant SKC functioning could be related to depression pathophysiology and diverts its late-life progression towards the development of AD. We summarize findings from preclinical and clinical studies suggesting a molecular linkage between depression and AD pathology. We also provide a rationale for considering SKCs as a novel pharmacological target for the treatment of AD-associated symptoms.
The Role of Vesicle Release and Synaptic Transmission in Depression
2022, NeuroscienceDepressive disorder is the leading cause of disability worldwide, yet the mechanisms underlying depression are not fully understood. Vesicle release is essential for synaptic neurotransmission, the abnormalities of vesicle release and synaptic plasticity are associated with various neuropsychiatric disorders. Neural circuits are ensembles of interconnected neurons that collectively perform specific functions. To some extent, depression may be caused by a disruption in the structural and functional connections of the neural circuits underlying emotion regulation. In this review, we summarized the role of abnormalities of vesicle release and synaptic transmission, as well as the related regulatory molecules and signal pathways in the regulation of depression.
Hippocampal orexin-1 and endocannabinoid-1 receptors underlie the kainate-induced occlusion in theta-burst long- term potentiation
2022, NeuropeptidesSeizures may result from the hyperexcitable neuronal activity of the brain. Multiple neurotransmitter receptors, including orexin (OX) and endocannabinoids interfere with forming the synaptic responses linked to the seizures. Therefore, this study investigates the involvement of OX-1 (OX1R) and endocannbinoid-1 (CB1R) receptors in the kainate- induced excitability in the synaptic field responses.
Theta pattern used to stimulate Schaffer collaterals and then metal microelectrodes to record the CA1 field excitatory postsynaptic potentials (fEPSPs). Input/ output stimulation and responses and paired- pulse (PP) stimuli employed to measure the state of synaptic activity in normal and kainate- induced seizure-like hyperexcitable activities and the slope of fEPSPs used as a measure of the change in the synaptic activity. Furthermore, agonists and antagonists of OX and endocannabinoids infused to investigate the involvement of their receptors.
The results showed that kainate application increased the fEPSP slope either in input stimuli with different intensities/output synaptic responses (I/O), or test pulse stimulated baseline synaptic responses (BSR) and, hence, increased the excitability of field responses in the CA1 region. However, neither kainate nor theta burst stimulation (TBS) could alter the PP stimuli -induced synaptic responses. TBS increased the fEPSP slope of the kainate-applied I/O and BSR, however, the increase was not high enough in BSR to be classified as long-term potentiation (LTP). The single-antagonist OX1R and CB1R administration prevented TBS- induced potentiation and partially recovered the effect by adding eCB or OX agonists in kainate-injected animals. In contrast, OX or combined eCB-OX antagonist application group demonstrated nearly full recovery of LTP induction.
Our study concludes that blockade of OX1 or CB1 prevents the induction of LTP, and OX infusion or both receptor blockade recovers the LTP.
Impaired learning and memory generated by hyperthyroidism is rescued by restoration of AMPA and NMDA receptors function
2022, Neurobiology of DiseaseHyperthyroidism has been identified as a risk factor for cognitive disorders. The hippocampus is a key brain region associated with cognitive function, among which excitatory synapse transmission plays an important role in the process of learning and memory. However, the mechanism by which hyperthyroidism leads to cognitive dysfunction through a synaptic mechanism remains unknown. We investigated the synaptic mechanisms in the effects of hyperthyroidism in an animal model that involved repeated injection of triiodothyronine (T3). These mice displayed impaired learning and memory in the Novel object recognition test, Y-maze test, and Morris Water Maze test, as well as elevated anxiety in the elevated plus maze. Mature dendritic spines in the hippocampal CA1 region of hyperthyroid mice were significantly decreased, accompanied by decreased level of AMPA- and NMDA-type glutamate receptors in the hippocampus. In primary cultured hippocampal neurons, levels of AMPA- and NMDA-type glutamate receptors also decreased and whole-cell patch-clamp recording revealed that excitatory synaptic function was obviously attenuated after T3 treatment. Notably, pharmacological activation of AMPAR or NMDAR by intraperitoneal injection of CX546, an AMPAR agonist, or NMDA, an NMDAR agonist can restore excitatory synaptic function and corrected impaired learning and memory deficit in hyperthyroid mice. Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and learning and memory disorders in hyperthyroidism.
Fading memories in aging and neurodegeneration: Is p75 neurotrophin receptor a culprit?
2022, Ageing Research ReviewsAging and age-related neurodegenerative diseases have become one of the major concerns in modern times as cognitive abilities tend to decline when we get older. It is well known that the main cause of this age-related cognitive deficit is due to aberrant changes in cellular, molecular circuitry and signaling pathways underlying synaptic plasticity and neuronal connections. The p75 neurotrophin receptor (p75NTR) is one of the important mediators regulating the fate of the neurons in the nervous system. Its importance in neuronal apoptosis is well documented. However, the mechanisms involving the regulation of p75NTR in synaptic plasticity and cognitive function remain obscure, although cognitive impairment has been associated with a higher expression of p75NTR in neurons. In this review, we discuss the current understanding of how neurons are influenced by p75NTR function to maintain normal neuronal synaptic strength and connectivity, particularly to support learning and memory in the hippocampus. We then discuss the age-associated alterations in neurophysiological mechanisms of synaptic plasticity and cognitive function. Furthermore, we also describe current evidence that has begun to elucidate how p75NTR regulates synaptic changes in aging and age-related neurodegenerative diseases, focusing on the hippocampus. Elucidating the role that p75NTR signaling plays in regulating synaptic plasticity will contribute to a better understanding of cognitive processes and pathological conditions. This will in turn provide novel approaches to improve therapies for the treatment of neurological diseases in which p75NTR dysfunction has been demonstrated.