Search

Notwithstanding major advances in psychotherapeutics, their efficacy and specificity remain limited. The slow onset of beneficial outcomes and numerous adverse effects of widely used medications remain of chief concern, warranting in-depth studies. The majority of frontline therapies are thought to enhance the endogenous monoaminergic drive, to initiate a cascade of molecular events leading to lasting functional and structural plasticity. They also involve alterations in trophic factor signalling, including brain-derived neurotrophic factor (BDNF), VGF (non-acronymic), vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), glial cell-derived neurotrophic factor (GDNF), and others. In several major mental disorders, emerging data suggest protective and restorative effects of trophic factors in preclinical models, when applied on their own. Antidepressant outcomes of VGF and FGF2, for instance, were shown in experimental animals, while BDNF and GDNF prove useful in the treatment of addiction, schizophrenia, and autism spectrum disorders. The main challenge with the effective translation of these and other findings in the clinic is the knowledge gap in action mechanisms with potential risks, as well as the lack of effective platforms for validation under clinical settings. Herein, we review the state-of-the-art and advances in the therapeutic use of trophic factors in several major neuropsychiatric disorders., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although produced largely in the periphery, gonadal steroids play a key role in regulating the development and functions of the central nervous system and have been implicated in several chronic neuropsychiatric disorders, with schizophrenia and Alzheimer's disease (AD) most prominent. Despite major differences in pathobiology and clinical manifestations, in both conditions, estrogen transpires primarily with protective effects, buffering the onset and progression of diseases at various levels. As a result, estrogen replacement therapy (ERT) emerges as one of the most widely discussed adjuvant interventions. In this review, we revisit evidence supporting the protective role of estrogen in schizophrenia and AD and consider putative cellular and molecular mechanisms. We explore the underlying functional processes relevant to the manifestation of these devastating conditions, with a focus on synaptic transmission and plasticity mechanisms. We discuss specific effects of estrogen deficit on neurotransmitter systems such as cholinergic, dopaminergic, serotoninergic, and glutamatergic. While the evidence from both, preclinical and clinical reports, in general, are supportive of the protective effects of estrogen from cognitive decline to synaptic pathology, numerous questions remain, calling for further research., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The disproportionate evolutionary expansion of the human cerebral cortex with reinforcement of cholinergic innervations warranted a major rise in the functional and metabolic load of the conserved basal forebrain (BF) cholinergic system. Given that acetylcholine (ACh) regulates properties of the microtubule-associated protein (MAP) tau and promotes non-amyloidogenic processing of amyloid precursor protein (APP), growing neocortex predicts higher demands for ACh, while the emerging role of BF cholinergic projections in Aβ clearance infers greater exposure of source neurons and their innervation fields to amyloid pathology. The higher exposure of evolutionary most recent cortical areas to the amyloid pathology of Alzheimer's disease (AD) with synaptic impairments and atrophy, therefore, might involve attenuated homeostatic effects of BF cholinergic projections, in addition to fall-outs of inherent processes of expanding association areas. This unifying model, thus, views amyloid pathology and loss of cholinergic cells as a quid pro quo of the allometric evolution of the human brain, which in combination with increase in life expectancy overwhelm the fine homeostatic balance and trigger the disease process., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Activation of the medial septum (MS) enhances the synchronized firing of pyramidal cells in the hippocampus. At least two distinct mechanisms might be recruited in this process: GABAergic inhibition of hippocampal inhibitory interneurons and cholinergic enhancement of pyramidal cell excitability. In the present study, a field potential recording in urethane anaesthetised rats was used to show that MS preconditioning with brief high-frequency burst stimulation markedly enhanced Schaffer collateral/commissural (SC/C) synaptically evoked population spikes in the CA1 area without significant alteration in the initial slope of SC/C field excitatory postsynaptic potentials (fEPSPs). An early phase (< approximately 125 ms) of the facilitation of neuronal discharge was inhibited by intracerebroventricular (i.c.v.) injection of the GABA(B) receptor antagonist CGP 52432 (200 nmol/5 microl). In contrast, the muscarinic cholinoceptor antagonist scopolamine (20 nmol/5 microl) inhibited a later phase ( approximately 150-300 ms) of the population spike facilitation. These findings support an important role for both cholinergic and GABAergic mediated septal drive in the tuning of signal conversion within the hippocampus as well as in securing the cortical feedback from the hippocampus.