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Perinatal asphyxia (PA) is an obstetric complication occurring when the oxygen supply to the newborn is temporally interrupted. This health problem is associated with high morbimortality in term and preterm neonates. It severely affects the brain structure and function, involving cortical, hippocampal, and striatal loss of neurons. Nearly 25% of PA survivor newborns develop several neurodevelopmental disabilities. Behavioral alterations, as well as the morphological and biochemical pathways involved in PA pathophysiology, have been studied using an animal model that resembles intrauterine asphyxia. Experimental evidence shows that PA induces synaptic derangement. Then, synaptic dysfunction embodies a putative target for neuroprotective strategies. Over the last years, therapeutic hypothermia (TH), the only treatment available, has shown positive results in the clinic. Several pharmacological agents are being tested in experimental or clinical trial studies to prevent synaptopathy. Preservation of the synaptic structure and function, i.e., “synaptoprotection,” makes up a promising challenge for reducing incidental neurodevelopmental disorders associated with PA. Accordingly, here, we summarize and review the findings obtained from the referred experimental model and propose a renewed overview in the field.

Abstract There is evidence that cognitive decline in Alzheimer's disease (AD) results from deficiencies in synaptic communication (e.g., loss of mushroom-shaped 'memory spines') and neurodegenerative processes. This might be treated with sigma-1 receptor (S1R) agonists, which are broadly neuroprotective and modulate synaptic plasticity. For example, we previously found that the mixed muscarinic/S1R agonist AF710B prevents mushroom spine loss in hippocampal cultures from APP knock-in (APP-KI) and presenilin-1-M146 V knock-in (PS1-KI) mice. We also found that the "dopaminergic stabilizer" pridopidine (structurally similar to the S1R agonist R(+)-3-PPP), is a high-affinity S1R agonist and is synaptoprotective in a mouse model of Huntington disease. Here we tested whether pridopidine and R(+)-3-PPP are synaptoprotective in models of AD and whether this requires S1R. We also examined the effects of pridopidine on long-term potentiation (LTP), endoplasmic reticulum calcium and neuronal store-operated calcium entry (nSOC) in spines, all of which are dysregulated in AD, contributing to synaptic pathology. We report here that pridopidine and 3-PPP protect mushroom spines from Aβ 42 oligomer toxicity in primary WT hippocampal cultures from mice. Pridopidine also reversed LTP defects in hippocampal slices resulting from application of Aβ 42 oligomers. Pridopidine and 3-PPP rescued mushroom spines in hippocampal cultures from APP-KI and PS1-KI mice. S1R knockdown from lenti-viral shRNA expression destabilized WT mushroom spines and prevented the synaptoprotective effects of pridopidine in PS1-KI cultures. Knockout of PS1/2 destabilized mushroom spines and pridopidine was unable to prevent this. Pridopidine lowered endoplasmic reticulum calcium levels in WT, PS1-KO, PS1-KI and PS2 KO neurons, but not in PS1/2 KO neurons. S1R was required for pridopidine to enhance spine nSOC in PS1-KI neurons. Pridopidine was unable to rescue PS1-KI mushroom spines during pharmacological or genetic inhibition of nSOC. Oral pridopidine treatment rescued mushroom spines in vivo in aged PS1-KI-GFP mice. Pridopidine stabilizes mushroom spines in mouse models of AD and this requires S1R, endoplasmic reticulum calcium leakage through PS1/2 and nSOC. Thus, pridopidine may be useful to explore for the treatment of AD. Highlights • Pridopidine stabilizes mushroom spines in Alzheimer's disease models. • Pridopidine rescues loss of LTP from amyloid-ß toxicity. • Mushroom spine stabilization by pridopidine requires sigma-1 receptor. • Pridopidine normalizes Ca2+ signaling alterations in PS1-KI hippocampal neurons. • Restoration of mushroom spines and calcium Ca2+ signaling requires PS1 and PS2. [ABSTRACT FROM AUTHOR]

Background Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease, which might underlie memory impairment. Our previous work demonstrates that magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we tested whether elevation of brain magnesium, using a recently developed compound (magnesium-L-threonate, MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic mouse model of Alzheimer's disease. Results MgT treatment reduced Aβ-plaque, prevented synapse loss and memory decline in the transgenic mice. Strikingly, MgT treatment was effective even when the treatment was given to the mice at the end-stage of their Alzheimer's disease-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brain of transgenic mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the transgenic mice, the NMDAR signaling pathway was downregulated, while the BACE1 expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression and reduced sAPPβ and β-CTF in the transgenic mice. At the molecular level, elevation of extracellular magnesium prevented the high Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Conclusions Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of Alzheimer's disease, and hence it might have therapeutic potential for treating Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: Despite numerous evidences for neurotoxicity of overexpressed α-synuclein, a protective function was suggested for endogenous α-synuclein and other members of the synuclein family. This protective role is most important for and evident in presynaptic terminals, where synucleins are normally accumulated. However, mice lacking synucleins display no adverse phenotype. In particular, no significant changes in striatal dopamine metabolism and only subtle deficit of dopaminergic neurons in the substantia nigra were found in juvenile or adult mice. To assess whether aging and synuclein deficiency may have additive detrimental effect on the nigrostriatal system, we studied dopaminergic neurons of the substantia nigra and their striatal synapses in 24–26-month-old α-synuclein and γ-synuclein null mutant mice. Significant ∼36% reduction of the striatal dopamine was found in aging α-synuclein, but not γ-synuclein null mutant mice when compared to age-matching wild type mice. This was accompanied by the reduction of TH-positive fibers in the striatum and decrease of striatal levels of TH and DAT. However, no progressive loss of TH-positive neurons was revealed in the substantia nigra of synuclein-deficient aging animals. Our results are consistent with a hypothesis that α-synuclein is important for normal function and integrity of synapses, and suggest that in the aging nervous system dysfunction of this protein could become a predisposition factor for the development of nigrostriatal pathology. [Copyright &y& Elsevier]

Perinatal asphyxia (PA) is an obstetric complication occurring when the oxygen supply to the newborn is temporally interrupted. This health problem is associated with high morbimortality in term and preterm neonates. It severely affects the brain structure and function, involving cortical, hippocampal, and striatal loss of neurons. Nearly 25% of PA survivor newborns develop several neurodevelopmental disabilities. Behavioral alterations, as well as the morphological and biochemical pathways involved in PA pathophysiology, have been studied using an animal model that resembles intrauterine asphyxia. Experimental evidence shows that PA induces synaptic derangement. Then, synaptic dysfunction embodies a putative target for neuroprotective strategies. Over the last years, therapeutic hypothermia (TH), the only treatment available, has shown positive results in the clinic. Several pharmacological agents are being tested in experimental or clinical trial studies to prevent synaptopathy. Preservation of the synaptic structure and function, i.e., "synaptoprotection," makes up a promising challenge for reducing incidental neurodevelopmental disorders associated with PA. Accordingly, here, we summarize and review the findings obtained from the referred experimental model and propose a renewed overview in the field., (Copyright © 2020 Herrera, Kobiec, Kölliker-Frers, Otero-Losada and Capani.)

By nature's original design, stress is a protective mechanism, signaling danger to homeostasis and, as a result, stimulating the brain to initiate coping and adaptive responses, which ultimately increases the chances of survival. On the other hand, stress may become a danger to homeostasis itself, when it is so severe or so prolonged that it overpowers cellular reserves. One of the consequences of traumatic stress is loss of hippocampal spine synapses, which is the main topic of this chapter summarizing research findings from the last 10+ years. Loss of spine synapses is thought to be a neuronal defense mechanism against excitotoxic damage, so the subcellular mechanisms of synapse loss are reviewed in the context of glutamatergic insults. One of the main conceptual derivates of stress-induced synaptic alterations is the "synaptogenic" hypothesis of major depressive disorder. The synaptogenic hypothesis postulates an inverse correlation between the number of limbic, mainly prefrontal cortical and hippocampal, spine synapses and the severity of depressive behavior/symptoms. The synaptogenic hypothesis implies that synaptoprotective interventions, that are capable of countering the stress-induced loss of limbic spine synapses, are probably also capable of promoting stress resilience, which may provide the conceptual basis for a preventive approach in antidepressant therapy. Finally, we discuss why electron microscopic stereology is a reliable and highly accurate technique for the quantitative assessment of ultrastructural particulate objects, such as spines and synapses., (© 2020 Elsevier Inc. All rights reserved.)