Volume 27, Issue 6

Experience-dependent changes in the strength of connections between neurons in the hippocampus (HPC) are critical for normal learning and memory consolidation, and disruption of this process drives a variety of neurological and psychiatric diseases. Proper HPC function relies upon discrete changes in gene expression driven by transcription factors (TFs) induced by neuronal activity. Here, we describe the induction and function of many of the most well-studied HPC TFs, including cyclic-AMP response element binding protein, serum-response factor, AP-1, and others, and describe their role in the learning process. We also discuss the known target genes of many of these TFs and the purported mechanisms by which they regulate long-term changes in HPC synaptic strength. Moreover, we propose that future research in this field will depend upon unbiased identification of additional gene targets for these activity-dependent TFs and subsequent meta-analyses that identify common genes or pathways regulated by multiple TFs in the HPC during learning or disease.

It is generally assumed at the time of this writing that memories are stored in the form of synaptic weights. However, it is now also clear that the synapses are not permanent; in fact, synaptic patterns undergo significant change in a matter of hours. This means that to implement the long survival of distant memories (for several decades in humans), the brain must possess a molecular backup mechanism in some form, complete with provisions for the storage and retrieval of information. It is found below that the memory-supporting molecules need not contain a detailed description of mental entities, as had been envisioned in the ‘memory molecule papers’ from 50 years ago, they only need to contain unique identifiers of various entities, and that this can be achieved using relatively small molecules, using a random code (‘ID molecules’). In this paper, the logistics of information flow are followed through the steps of storage and retrieval, and the conclusion reached is that the ID molecules, by carrying a sufficient amount of information (entropy), can effectively control the recreation of complex multineuronal patterns. In illustrations, it is described how ID molecules can be made to revive a selected cell assembly by waking up its synapses and how they cause a selected cell assembly to ignite by sending slow inward currents into its cells. The arrangement involves producing multiple copies of the ID molecules and distributing them at strategic locations at selected sets of synapses, then reaching them through small noncoding RNA molecules. This requires the quick creation of entropy-rich messengers and matching receptors, and it suggests that these are created from each other by small-scale transcription and reverse transcription.

Experimental evidence has demonstrated that glutamate is an essential factor for neurogenesis, whereas another line of research postulates that excessive glutamatergic neurotransmission is associated with the pathogenesis of depression. The present review shows that such paradox can be explained within the framework of hormesis, defined as biphasic dose responses. Low glutamate levels activate adaptive stress responses that include proteins that protect neurons against more severe stress. Conversely, abnormally high levels of glutamate, resulting from increased release and/or decreased removal, cause neuronal atrophy and depression. The dysregulation of the glutamatergic transmission in depression could be underlined by several factors including a decreased inhibition (γ-aminobutyric acid or serotonin) or an increased excitation (primarily within the glutamatergic system). Experimental evidence shows that the activation of N -methyl-D-aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) can exert two opposite effects on neurogenesis and neuron survival depending on the synaptic or extrasynaptic concentration. Chronic stress, which usually underlies experimental and clinical depression, enhances glutamate release. This overactivates NMDA receptors (NMDAR) and consequently impairs AMPAR activity. Various studies show that treatment with antidepressants decreases plasma glutamate levels in depressed individuals and regulates glutamate receptors by reducing NMDAR function by decreasing the expression of its subunits and by potentiating AMPAR-mediated transmission. Additionally, it has been shown that chronic treatment with antidepressants having divergent mechanisms of action (including tricyclics, selective serotonin reuptake inhibitors, and ketamine) markedly reduced depolarization-evoked glutamate release in the hippocampus. These data, taken together, suggest that the glutamatergic system could be a final common pathway for antidepressant treatments.

The blood-brain barrier (BBB) is a protective structure that helps maintaining the homeostasis in cerebral microenvironment by limiting the passage of molecules into the brain. BBB is formed by closely conjugated endothelial cells, with astrocytic endfeet surrounded and extracellular matrix (ECM) consolidated. Numerous neurological diseases can cause disturbance of BBB, leading to brain edema and neurological dysfunctions. The low-density lipoprotein (LDL) receptor–related protein 1 (LRP-1), a member of the LDL receptor gene family, is involved in a lot of important processes in the brain under both physiological and pathological conditions. As a membrane receptor, LRP-1 interacts with a variety of ligands and mediates the internalization of several important substances. LRP-1 is found responsible for inducing the opening of BBB following ischemic attack. It has also been reported that LRP-1 regulates several tight junction proteins and mediates the clearance of major ECM-degrading proteinases. In this review, we briefly discussed the role of LRP-1 in regulating BBB integrity by modulating tight junction proteins, endothelial cells and the remodeling of ECM.

Although the role of inflammation in neurodegeneration has been well acknowledged, less is known on the issue of each cytokine in specific neurodegenerative diseases. In this review, we will present evidence elucidating that interleukin-1β (IL-1β) has a multi-faceted character in pathogenesis of Parkinson’s disease, which is a progressive neurodegenerative disorder. Increased levels of IL-1β were found in PD patients. Besides, PD symptoms were observed in IL-1β wild-type, but not deficient, animals. These lines of evidence suggest that IL-1β may contribute to the initiation or progression of PD. On the other hand, some studies reported decreased levels of IL-1β in PD patients. Also, genetic studies provided evidence suggesting that IL-1β may protect individuals against PD. Presumably, the broad range of IL-1β role is due to its interaction with both upstream and downstream mediators. Differences in IL-1β levels could be because of glia population (i.e. microglia and astrocytes), mitogen-activated protein kinase and nuclear factor κ light-chain-enhancer of activated B cells signaling pathways, and several mediators (including cyclooxygenase, neurotrophic factors, reactive oxygen species, caspases, heme oxygenase-1, and matrix metalloproteinases). Although far from practice at this point, unraveling theoretical therapeutic targets based on the up-down IL-1β neuroweb could facilitate the development of strategies that are likely to be used for pharmaceutical designs of anti-neurodegenerative drugs of the future.

Parkinson’s disease (PD) is the second most common chronic neurodegenerative disease that affects motor skills and cognitive performance. The conventional therapeutic approaches for the management of PD are just able to alleviate symptoms. Exploring for achieving novel substances with therapeutic benefits in PD patients is the focus of a wide range of current investigations. The aim of the present study is to comprehensively review phytochemicals with protective or therapeutic activities in PD and focus on their neuropsychopharmacological mechanisms. Various subgroups of polyphenols (flavonoids, phenolic acids, stilbenes, and lignanes) and terpenes are the most abundant groups of phytochemicals with well-established antiparkinsonian effects. Other phytochemical categories, such as alkaloids, cinnamates, carbohydrates, amino acids, and fatty acid amides, also have some representatives with positive effects in PD. Phytochemicals perform their antiparkinsonian effect through several mechanisms of action, including suppressing apoptosis (via the reduction of Bax/Bcl-2, caspase-3, -8, and -9, and α-synuclein accumulation), decreasing dopaminergic neuronal loss and dopamine depletion, reducing the expression of proinflammatory cytokines (such as prostaglandin E 2 , interleukin-6, interleukin-1β, and nuclear factor-κB), and modulating nuclear and cellular inflammatory signaling, elevation of neurotrophic factors, and improvement of antioxidant status. Plant-derived natural products can be considered as future pharmaceutical drugs or adjuvant treatment with conventional therapeutic approaches to improve their efficacy and alleviate their psychological adverse effects in the management of PD. Well-designed clinical trials are mandatory to evaluate the protective and healing benefits of phytochemicals as promising future drugs in the management of neurodegenerative diseases.