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The synaptogenic hypothesis of major depressive disorder implies that preventing the onset of depressive-like behavior also prevents the loss of hippocampal spine synapses. By applying the psychoactive drugs, diazepam and fluoxetine, we investigated whether blocking the development of helpless behavior by promoting stress resilience in the rat learned helplessness paradigm is associated with a synaptoprotective action in the hippocampus. Adult ovariectomized and intact female Sprague-Dawley rats (n = 297) were treated with either diazepam, fluoxetine, or vehicle, exposed to inescapable footshocks or sham stress, and tested in an active escape task to assess helpless behavior. Escape-evoked corticosterone secretion, as well as remodeling of hippocampal spine synapses at a timepoint representing the onset of escape testing were also analyzed. In ovariectomized females, treatment with diazepam prior to stress exposure prevented helpless behavior, blocked the loss of hippocampal spine synapses, and muted the corticosterone surge evoked by escape testing. Although fluoxetine stimulated escape performance and hippocampal synaptogenesis under non-stressed conditions, almost all responses to fluoxetine were abolished following exposure to inescapable stress. Only a much higher dose of fluoxetine was capable of partly reproducing the strong protective actions of diazepam. Importantly, these protective actions were retained in the presence of ovarian hormones. Our findings indicate that stress resilience is associated with the preservation of spine synapses in the hippocampus, raising the possibility that, besides synaptogenesis, hippocampal synaptoprotection is also implicated in antidepressant therapy., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hypoxic circumstances result in functional and structural impairments of the brain. Oxygen-glucose deprivation (OGD) on hippocampal slices is a technique widely used to investigate the consequences of ischemic stroke and the potential neuroprotective effects of different drugs. Acetyl-l-carnitine (ALC) is a naturally occurring substance in the body, and it can therefore be administered safely even in relatively high doses. In previous experiments, ALC pretreatment proved to be effective against global hypoperfusion. In the present study, we investigated whether ALC can be protective in an OGD model. We are not aware of any earlier study in which the long-term potentiation (LTP) function on hippocampal slices was measured after OGD. Therefore, we set out to determine whether an effective ALC concentration has an effect on synaptic plasticity after OGD in the hippocampal CA1 subfield of rats. A further aim was to investigate the mechanism underlying the protective effect of this compound. The experiments revealed that ALC is neuroprotective against OGD in a dose-dependent manner, which is manifested not only in the regeneration of the impaired synaptic transmission after the OGD, but also in the inducibility and stability of the LTP. In the case of the most effective concentration of ALC (500μM), use of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) revealed that the PI3K/Akt signaling pathway has a key role in the restoration of the synaptic transmission and plasticity reached by ALC treatment., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Long-chain polyunsaturated fatty acid (LC-PUFA) composition of neural membranes is a key factor for brain development, in chemical communication of neurons and probably also their survival in response to injury. Viability of cholinergic neurons was tested during brain development following dietary supplementation of fish oil LC-PUFAs (docosahexaenoic acid [DHA], eicosapentaenoic acid, arachidonic acid) in the food of mother rats. Excitotoxic injury was introduced by N-methyl-D,L-aspartate (NMDA) injection into the cholinergic nucleus basalis magnocellularis of 14-day-old rats. The degree of loss of cholinergic cell bodies, and the extend of axonal and dendritic disintegration were measured following immunocytochemical staining of cell bodies and dendrites for choline acetyltransferase and p75 low-affinity neurotrophin receptor and by histochemical staining of acetylcholinesterase-positive fibres in the parietal neocortex. The impact of different feeding regimens on fatty acid composition of neural membrane phospholipids was also assayed at 12 days of age. Supplementation of LC-PUFAs resulted in a resistance against NMDA-induced excitotoxic degeneration of cholinergic neurones in the infant rats. More cholinergic cells survived, the dendritic involution of surviving neurons in the penumbra region decreased, and the degeneration of axons at the superficial layers of parietal neocortex also attenuated after supplementing LC-PUFAs. A marked increment in DHA content in all types of phospholipids was obtained in the forebrain neuronal membrane fraction of supplemented rats. It is concluded that fish oil LC-PUFAs, first of all DHA, is responsible for the neuroprotective action on developing cholinergic neurons against glutamate cytotoxicity.