Plasticity In Mouse Hippocampus Research Articles

Proteomic analysis involved with synaptic plasticity improvement by GABAA receptor blockade in hippocampus of a mouse model of Alzheimer’s disease

GABAergic system plays a part in synaptic plasticity in the hippocampus. We had reported a long-term potentiation (LTP)-like facilitation in vivo, known as synaptic plasticity, through GABAA receptor blockade by bicuculline and the expression of proteins involved with this synaptic plasticity in mouse hippocampus. In the present study, we aimed to show improvement of impaired synaptic plasticity through GABAA receptor blockade and to clarify the molecular mechanisms involved with this improvement in the hippocampus of mice overexpressing human amyloid precursor protein with the E693Δ mutation (APPOSK-Tg) as an Alzheimer’s disease model showing impaired synaptic plasticity. Electrophysiological study showed that the LTP-like facilitation expressed with application of bicuculline in vivo was significantly greater than impaired tetanic LTP in APPOSK-Tg mice, which was improved by bicuculline. Proteomic analysis showed that the expression of 11 proteins in the hippocampus was significantly changed 8 h after bicuculline application to APPOSK-Tg mice. The identified proteins could be functionally classified as chaperone, cytoskeletal protein, energy metabolism, metabolism, neuronal development, and synaptic component. Additionally, western blotting validated the changes in four proteins. We therefore propose that the improvement of impaired synaptic plasticity through GABAA receptor blockade could be mediated by the changed expression of these proteins.

Effects of chronic mild stress induced depression on synaptic plasticity in mouse hippocampus.

Chronic mild stress (CMS) model is most similar to the depression human suffered in daily life. Strong evidence proved the important role of hippocampal synaptic plasticity in the mechanism of depression. This study investigated the effect of CMS on synaptic plasticity in hippocampus. Our results showed that CMS impaired spatial memory and exploring ability, disturbed the release of neurotransmitters including 5-hydroxytryptamine (5-HT) and dopamine (DA), reduced the density of synaptic vesicle in inner molecular layer, increased the number of thin spines in inner and outer molecular layer, whereas did not affect the density of spine apparatus, the above mentioned were probably related to the reduction of astrocytes and activation of microglial cells.

Contradictory effects of erythropoietin on inhibitory synaptic transmission in left and right prelimbic cortex of mice

Erythropoietin (EPO) has been shown to improve cognitive function in mammals as well as in patients of psychiatric diseases by directly acting on the brain. In addition, EPO attenuates the synaptic transmission and enhances short- and long-term synaptic plasticity in hippocampus of mice, although there are still many discrepancies between different studies. It has been suggested that the divergences of different studies take root in different in-vivo application schemata or in long-term trophic effects of EPO. In the current study, we investigated the direct effects of EPO in slices of prelimbic cortex (PrL) by acute ex-vivo application of EPO, so that the erythropoietic or other trophic effects could be entirely excluded. Our results showed that the EPO effects were contradictory between the left and the right PrL. It enhanced the inhibitory transmission in the left and depressed the inhibitory transmission in the right PrL. Strikingly, this lateralized effect of EPO could be consistently found in individual bi-lateral PrL of all tested mice. Thus, our data suggest that EPO differentially modulates the inhibitory synaptic transmission of neuronal networks in the left and the right PrL. We hypothesize that such lateralized effects of EPO contribute to the development of the lateralization of stress reaction in PFC and underlie the altered bilateral GAGAergic synaptic transmission and oscillation patterns under stress that impact the central emotional and cognitive control in physiology as well as in pathophysiology.

Effects of neonatal exposure to the flame retardant tetrabromobisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term potentiation and synaptic protein levels in mice.

Brominated flame retardants such as tetrabromobisphenol-A (TBBPA) may exert (developmental) neurotoxic effects. However, data on (neuro)toxicity of halogen-free flame retardants (HFFRs) are scarce. Recent in vitro studies indicated a high neurotoxic potential for some HFFRs, e.g., zinc stannate (ZS), whereas the neurotoxic potential of other HFFRs, such as aluminum diethylphosphinate (Alpi), appears low. However, the in vivo (neuro)toxicity of these compounds is largely unknown. We therefore investigated effects of neonatal exposure to TBBPA, Alpi or ZS on synaptic plasticity in mouse hippocampus. Male C57bl/6 mice received a single oral dose of 211 µmol/kg bw TBBPA, Alpi or ZS on postnatal day (PND) 10. On PND 17-19, effects on hippocampal synaptic plasticity were investigated using ex vivo extracellular field recordings. Additionally, we measured levels of postsynaptic proteins involved in long-term potentiation (LTP) as well as flame retardant concentrations in brain, muscle and liver tissues. All three flame retardants induced minor, but insignificant, effects on LTP. Additionally, TBBPA induced a minor decrease in post-tetanic potentiation. Despite these minor effects, expression of selected synaptic proteins involved in LTP was not affected. The flame retardants could not be measured in significant amounts in the brains, suggesting low bioavailability and/or rapid elimination/metabolism. We therefore conclude that a single neonatal exposure on PND 10 to TBBPA, Alpi or ZS does affect neurodevelopment and synaptic plasticity only to a small extent in mice. Additional data, in particular on persistence, bioaccumulation and (in vivo) toxicity, following prolonged (developmental) exposure are required for further (human) risk assessment.

Differential neuronal plasticity in mouse hippocampus associated with various periods of enriched environment during postnatal development.

Enriched environment (EE) is characterized by improved conditions for enhanced exploration, cognitive activity, social interaction and physical exercise. It has been shown that EE positively regulates the remodeling of neural circuits, memory consolidation, long-term changes in synaptic strength and neurogenesis. However, the fine mechanisms by which environment shapes the brain at different postnatal developmental stages and the duration required to induce such changes are still a matter of debate. In EE, large groups of mice were housed in bigger cages and were given toys, nesting materials and other equipment that promote physical activity to provide a stimulating environment. Weaned mice were housed in EE for 4, 6 or 8weeks and compared with matched control mice that were raised in a standard environment. To investigate the differential effects of EE on immature and mature brains, we also housed young adult mice (8weeks old) for 4weeks in EE. We studied the influence of onset and duration of EE housing on the structure and function of hippocampal neurons. We found that: (1) EE enhances neurogenesis in juvenile, but not young adult mice; (2) EE increases the number of synaptic contacts at every stage; (3) long-term potentiation (LTP) and spontaneous and miniature activity at the glutamatergic synapses are affected differently by EE depending on its onset and duration. Our study provides an integrative view of the role of EE during postnatal development in various mechanisms of plasticity in the hippocampus including neurogenesis, synaptic morphology and electrophysiological parameters of synaptic connectivity. This work provides an explanation for discrepancies found in the literature about the effects of EE on LTP and emphasizes the importance of environment on hippocampal plasticity.

The expression changes of EphA3 receptor during synaptic plasticity in mouse hippocampus through activation of nicotinic acetylcholine receptor

We have reported that systemic application of nicotinic agonists results in expression of a long-term potentiation-like facilitation, a model of synaptic plasticity, in the mouse hippocampus in vivo. Eph receptors and their ephrin ligands, are thought to participate in synaptic plasticity. The present study was conducted to clarify the involvement of EphA3 receptor in synaptic plasticity by investigating the time-dependent change of the expression levels of EphA3 receptor during long-term potentiation-like facilitation in the mouse hippocampus. EphA3 receptor mRNA and protein expression was found in adult mouse hippocampus. EphA3 receptor was localized in neuronal cells but not astrocytes or microglia of hippocampus. After intraperitoneal application of nicotine (3 mg/kg), the protein expression of EphA3 receptor in hippocampus increased during 2-24-h period, significantly increasing during 2-12-h period, and finally returned to the basal level in 72 h, although the mRNA expression of EphA3 receptor was not changed for 24 h. This enhanced expression of EphA3 receptor protein at 4 h was inhibited by pretreatment of mecamylamine (0.5 mg/kg, intraperitoneally), a nonselective nicotinic acetylcholine receptor antagonist. Our findings demonstrated that EphA3 receptor localized only in neuronal cells of the hippocampus was enhanced without transcriptional regulation during synaptic plasticity through activation of the nicotinic acetylcholine receptor. These results suggest that the enhancement of EphA3 receptor after synaptic plasticity may contribute to long-lasting synaptic plasticity through positive, feedforward mechanisms.

Synaptotagmin1 synthesis induced by synaptic plasticity in mouse hippocampus through activation of nicotinic acetylcholine receptors

We have reported that systemic application of nicotinic agonists expresses a long-term potentiation (LTP)-like facilitation, a model of synaptic plasticity, in vivo in the mouse hippocampus. The present study conducted to clarify the involvement of synaptotagmin1 in synaptic plasticity by investigating the time-dependent change of the mRNA and protein levels of synaptotagmin1 during LTP-like facilitation in the mouse hippocampus. The mRNA expression of synaptotagmin1 increased during 2- to 8-h period by intraperitoneal application of nicotine (3 mg/kg), returning to the basal level in 12-h. Also, the protein level of synaptotagmin1, but not synaptophysin, in a total fraction from hippocampus increased during 4- to 12-h period by the same treatment, returning to the basal level in 24-h. The protein level of synaptotagmin1 in a membrane fraction from hippocampus also increased during 4- to 8-h period by nicotine, returning to the basal level in 12-h. This nicotine-enhanced synaptotagmin1 protein in a membrane fraction was inhibited by pretreatment of mecamylamine (0.3 mg/kg, i.p.), a nonselective nicotinic acetylcholine receptors (nAChRs) antagonist. Furthermore, choline (30 mg/kg, i.p.), a selective α7 nAChR agonist, or ABT-418 (10 mg/kg, i.p.), a selective α4β2 nAChR agonist, enhanced the level of synaptotagmin1 in a membrane fraction. Our findings demonstrate that synaptotagmin1 protein following mRNA which is enhanced without increasing the number of synapse gathers around pre-synaptic membrane during hippocampal LTP-like facilitation through activation of α7 and/or α4β2 nAChRs in the brain. These results suggest that new-synthesized synaptotagmin1 following synaptic plasticity may contribute to long-lasting synaptic plasticity via positive, feedfoward mechanisms.