Reduction In Synaptic Plasticity Research Articles

E3 Ubiquitin Ligase Uhrf2 Knockout Reveals a Critical Role in Social Behavior and Synaptic Plasticity in the Hippocampus.

The hippocampal formation, particularly the CA2 subregion, is critical for social memory formation and memory processing, relying on synaptic plasticity-a fundamental mechanism by which synapses strengthen. Given the role of the ubiquitin-proteasome system (UPS) in various nervous system processes, including learning and memory, we were particularly interested in exploring the involvement of RING-type ubiquitin E3 ligases, such as UHRF2 (NIRF), in social behavior and synaptic plasticity. Our results revealed altered social behavior in mice with systemic Uhrf2 knockout, including changes in nest building, tube dominance, and the three-chamber social novelty test. In Uhrf2 knockout mice, the entorhinal cortex-CA2 circuit showed significant reductions in synaptic plasticity during paired-pulse facilitation and long-term potentiation, while the inability to evoke synaptic plasticity in the Schaffer-collateral CA2 synapses remained unaffected. These changes in synaptic plasticity correlated with significant changes in gene expression including genes related to vesicle trafficking and transcriptional regulation. The effects of Uhrf2 knockout on synaptic plasticity and the observed gene expression changes highlight UHRF2 as a regulator of learning and memory processes at both the cellular and systemic levels. Targeting E3 ubiquitin ligases, such as UHRF2, may hold therapeutic potential for memory-related disorders, warranting further investigation.

Overexpressing glyoxalase 1 attenuates acute hyperglycemia–exacerbated neurological deficits of ischemic stroke in mice

Stress-induced hyperglycemia (SIH) is associated with poor functional recovery and high mortality in patients with acute ischemic stroke (AIS). However, intensive controlling of blood glucose by using insulin was not beneficial in patients with AIS and acute hyperglycemia. This study investigated the therapeutic effects of the overexpression of glyoxalase I (GLO1), a detoxifying enzyme of glycotoxins, on acute hyperglycemia–aggravated ischemic brain injury. In the present study, adeno-associated viral (AAV)-mediated GLO1 overexpression reduced infarct volume and edema level but did not improve neurofunctional recovery in the mice with middle cerebral artery occlusion (MCAO). AAV-GLO1 infection significantly enhanced neurofunctional recovery in the MCAO mice with acute hyperglycemia but not in the mice with normoglycemia. Methylglyoxal (MG)-modified proteins expression significantly increased in the ipsilateral cortex of the MCAO mice with acute hyperglycemia. AAV-GLO1 infection attenuated the induction of MG-modified proteins, ER stress formation, and caspase 3/7 activation in MG-treated Neuro-2A cells, and reductions in synaptic plasticity and microglial activation were mitigated in the injured cortex of the MCAO mice with acute hyperglycemia. Treatment with ketotifen, a potent GLO1 stimulator, after surgery, alleviated neurofunctional deficits and ischemic brain damage in the MCAO mice with acute hyperglycemia. Altogether, our data substantiate that, in ischemic brain injury, GLO1 overexpression can alleviate pathologic alterations caused by acute hyperglycemia. Upregulation of GLO1 may be a therapeutic strategy for alleviating SIH-aggravated poor functional outcomes in patients with AIS.

0116 Slow oscillations promote long range effective communication: the key for memory consolidation in a broken down network

Abstract Introduction The relation between slow oscillations (SOs, <1Hz) during non-rapid eye movement (NREM) sleep and systems-level memory consolidation is one of the most robust findings in cognitive neuroscience. However, NREM is a brain state seemingly unfavorable to systems consolidation because a hallmark characteristic of this state is a breakdown in connectivity and reduction in synaptic plasticity with increasing depth of sleep. Our study addresses this apparent paradox and how SOs orchestrate neural communication. Methods We employed generalized partial directed coherence to estimate directional causal information flow between EEG channels across the electrode manifold during SO and non-SO periods. We examined the magnitude of causal information flow over the phase of SOs and found two peaks of flow preceding and following the trough of the SO. We categorized source-sink pairs of flows into three groups based on distance between source and sink of information flow. All the peak flows in each group were averaged and we tested relation between averaged magnitude of the flow and overnight episodic memory improvement using correlation test. Results The results reveal that NREM generally (non-SO periods) and during the SO trough show dampened neural communication. Causal communication during non-rapid eye movement sleep peaks during specific phases of the SO ( before and after SO trough), but only across long distances. Correlation test results showed that episodic memory improvement was predicted by peaks of information flow with longest distances between sinks and sources, and not by any other phase of the SO or non-SO period. Conclusion This work introduces a non-invasive approach to examine information processing during sleep, a behavioral stage whose function, until now, has been understood only at a delay. The findings represent a conceptual leap in understanding how slow oscillations unlock memory consolidation in a broken down network which is by promoting long range effective communication. This research will promote further investigations of understanding how brain oscillations alone and in nested rhythms promote network communication, as well as to investigate how these properties vary and predict patterns of deficits in clinical populations and aging humans. Support (If Any)

Bisphenol-A Exposure during Gestation and Lactation Causes Visual Perception Deficits in Rat Pups Following a Decrease in Interleukin 1β Expression in the Primary Visual Cortex

Bisphenol-A (BPA) exposure can affect cognitive functions of rodents and humans. However, whether information inputs for these functions in the brain are perturbed by BPA remains unclear. Here, visual perception in rats was assessed by testing their ability to discriminate between vertical and horizontal grating. We found that BPA exposure (1 mg/kg/day) during gestation and lactation markedly decreased the grating discrimination ability in rat pups (postnatal 21 days). The results of neuronal functions in the primary visual cortex (V1) showed that the orientation selectivity and signal extraction ability and fidelity were notably decreased after BPA exposure. These effects were accompanied by a reduction in synaptic plasticity (i.e., spine density and maturity) in the V1. According to inflammatory factor expression and glial cell morphology, no increase in inflammatory activation was observed after BPA exposure. However, BPA-exposed rat pups exhibited a significant decrease in IL-1β expression in the V1, accompanied by a decline in P38 phosphorylation. After local injection of IL-1β (10 ng/ml) in the V1, these two visual properties recovered to normal levels. Thus, our findings imply that physiological dysfunction of IL-1β may contribute to orientation perception deficits in BPA-exposed rats.

Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer's disease.

Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1-42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.

Loss of Perineuronal Net in ME7 Prion Disease

Microglial activation and behavioral abnormalities occur before neuronal loss in experimental murine prion disease; the behavioral changes coincide with a reduction in synaptic plasticity. Because synaptic plasticity depends on an intact perineuronal net (PN), a specialized extracellular matrix that surrounds parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid [GABA]) inhibitory interneurons, we investigated the temporal relationships between microglial activation and loss of PN and PV-positive neurons in ME7 murine prion disease. Anesthetized C57Bl/6J mice received bilateral intracerebral microinjections of ME7-infected or normal brain homogenate into the dorsal hippocampus. Microglial activation, PrP accumulation, the number of PV-positive interneurons, and Wisteria floribunda agglutinin-positive neurons (i.e. those with an intact PN) were assessed in the ventral CA1 and subiculum at 4, 8, 12, 16, and 20 weeks postinjection. Hippocampal areas and total neuron numbers in the ventral CA1 and subiculum were also determined. Loss of PN coincided with early microglial activation and with a reduction in synaptic plasticity. No significant loss of PV-positive interneurons was observed. Our findings suggest that the substrate of the earliest synaptic and behavioral abnormalities in murine prion disease may be inflammatory microglia-mediated degradation of the PN.

Differential effect of aging on synaptic plasticity in the ventral and dorsal striatum

Both the ventral and dorsal striatum are involved in various forms of motor, motivational and learning behaviors. Previously, we demonstrated that several striatum-dependent motor and learning behaviors were reduced in mice with increased age. In this study, we investigated the effects of aging on synaptic plasticity in brain slices containing the nucleus accumbens (NAc) or caudate-putamen (CPu), using electrophysiological recordings. We showed that long-term depression (LTD) was reduced or absent in the NAc of aged C57BL/6 mice, whereas the amount of LTD in the CPu of young and aged mice was similar. The LTD induced by 10-Hz stimulation is NMDAR-dependent in the NAc, but NMDAR-independent in the CPu. Our results suggest that NAc LTD may be more sensitive than CPu LTD to the effects of normal aging with a possibility that NMDAR-dependent LTD may be more susceptible to the aging process than non-NMDAR LTD. We also showed that paired-pulse facilitation was diminished in the NAc and CPu in aged mice, suggesting that aging is accompanied by significant decline in presynaptic function in both the ventral and dorsal striata. The age-related reduction in synaptic plasticity may be a cellular mechanism underlying the age-related impairments in striatum-dependent motor and cognitive functions.

Presynaptic plasticity and associative learning are impaired in a Drosophila presenilin null mutant

Alzheimer's disease is a neurodegenerative disorder characterized by progressive memory and cognitive decline that is associated with changes in synaptic plasticity and neuronal cell loss. Recent evidence suggests that some of these defects may be due to a loss of normal presenilin activity. Here, we have examined the effect of loss of Drosophila presenilin (psn) function on synaptic plasticity and learning. Basal transmitter release was elevated in psn mutants while both paired pulse synaptic plasticity and post-tetanic potentiation were impaired. These defects in synaptic strength and plasticity were not due to developmental defects in NMJ morphology. We also found that psn null terminals take up significantly less FM 4-64 than control terminals when loaded with high frequency stimulation, suggesting a defect in synaptic vesicle availability or mobilization. To determine whether these reductions in synaptic plasticity had any impact on learning, we tested the larvae for defects in associative learning. Using both olfactory and visual learning assays, we found that associative learning is impaired in psn mutants compared with controls. Both the learning and synaptic defects could be rescued by expression of a full length psn transgene suggesting the defects are specifically due to a loss of psn function. Taken together, these results provide the first evidence of learning and synaptic defects in a Drosophila psn mutant and strongly suggest a presynaptic role for presenilin in normal neuronal function.

Structure of Synaptophysin: A Hexameric MARVEL-Domain Channel Protein

Synaptophysin I (SypI) is an archetypal member of the MARVEL-domain family of integral membrane proteins and one of the first synaptic vesicle proteins to be identified and cloned. Most all MARVEL-domain proteins are involved in membrane apposition and vesicle-trafficking events, but their precise role in these processes is unclear. We have purified mammalian SypI and determined its three-dimensional (3D) structure by using electron microscopy and single-particle 3D reconstruction. The hexameric structure resembles an open basket with a large pore and tenuous interactions within the cytosolic domain. The structure suggests a model for Synaptophysin's role in fusion and recycling that is regulated by known interactions with the SNARE machinery. This 3D structure of a MARVEL-domain protein provides a structural foundation for understanding the role of these important proteins in a variety of biological processes.

Reducing the Variability of Neural Responses: A Computational Theory of Spike-Timing-Dependent Plasticity

Experimental studies have observed synaptic potentiation when a presynaptic neuron fires shortly before a postsynaptic neuron and synaptic depression when the presynaptic neuron fires shortly after. The dependence of synaptic modulation on the precise timing of the two action potentials is known as spike-timing dependent plasticity (STDP). We derive STDP from a simple computational principle: synapses adapt so as to minimize the postsynaptic neuron's response variability to a given presynaptic input, causing the neuron's output to become more reliable in the face of noise. Using an objective function that minimizes response variability and the biophysically realistic spike-response model of Gerstner (2001), we simulate neurophysiological experiments and obtain the characteristic STDP curve along with other phenomena, including the reduction in synaptic plasticity as synaptic efficacy increases. We compare our account to other efforts to derive STDP from computational principles and argue that our account provides the most comprehensive coverage of the phenomena. Thus, reliability of neural response in the face of noise may be a key goal of unsupervised cortical adaptation.