Decrease In Long-term Potentiation Research Articles

Impact of Sleep Deprivation on the Brain’s Inflammatory Response Triggered by Lipopolysaccharide and Its Consequences on Spatial Learning and Memory and Long-Term Potentiation in Male Rats

Introduction: Both sleep deprivation (SD) and inflammation can negatively affect cognitive function. This study aimed to investigate how SD impacts the brain’s inflammatory response to lipopolysaccharide (LPS) and its subsequent effects on cognitive functions. Methods: To this end, male rats were tested through a Morris water maze (MWM) to assess their spatial learning and memory. Also, in vivo field potential recordings (to evaluate synaptic plasticity) were done in the Saline, SD, LPS1 (1 mg/kg/7 days), and LPS1+SD groups. Cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Based on the results, the LPS1+SD group showed increased total distance and escape latency compared to the other groups in the MWM test. Besides, the LPS1+SD group exhibited a significant decrease in long-term potentiation (LTP) induction and maintenance in the CA1 area of the brain. Finally, the inflammatory cytokine interleukin-1β (IL-1β) levels were significantly higher in the LPS1+SD group than in the Saline group. Conclusion: These findings suggest that the combined effects of SD and brain inflammatory response can have more harmful effects on cognitive function, LTP, and inflammatory factors than either SD or LPS1 alone.

Facial nerve axotomy induces morphological changes in hippocampal pyramidal neurons.

Facial nerve injury in rats have been widely used to study functional and structural changes that occur in the injured motoneurons and other central nervous system structures related with sensorimotor processing. A decrease in long-term potentiation of hippocampal CA3-to-CA1 commissural synapse has recently been reported related to this peripheral injury. Additionally, it has been found increased corticosterone plasmatic levels, impairment in spatial memory consolidation, and hippocampal microglial activation in animals with facial nerve axotomy. In this work, we analyzed the neuronal morphology of hippocampal CA1 and CA3 pyramidal neurons in animals with either reversible or irreversible facial nerve injury. For this purpose, brain tissues of injured animals sacrificed at different postlesion times, were stained with the Golgi-Cox method and compared with control brains. It was found that both reversible and irreversible facial nerve injury-induced significant decreases in dendritic tree complexity, dendritic length, branch points, and spine density of hippocampal neurons. However, such changes' timing varied according to hippocampal area (CA1 vs. CA3), dendritic area (apical vs. basal), and lesion type (reversible vs. irreversible). In general, the observed changes were transient when animals had the possibility of motor recovery (reversible injury), but perdurable if the recovery from the lesion was impeded (irreversible injury). CA1 apical and CA3 basal dendritic tree morphology were more sensible to irreversible injury. It is concluded that facial nerve injury induced significant changes in hippocampal CA1 and CA3 pyramidal neurons morphology, which could be related to LTP impairments and microglial activation in the hippocampal formation, previously described.

Partial Depletion of Microglia Attenuates Long-Term Potentiation Deficits following Repeated Blast Traumatic Brain Injury in Organotypic Hippocampal Slice Cultures.

Blast-induced traumatic brain injury (bTBI) has been a health concern in both military and civilian populations due to recent military and geopolitical conflicts. Military service members are frequently exposed to repeated bTBI throughout their training and deployment. Our group has previously reported compounding functional deficits as a result of increased number of blast exposures. In this study, we further characterized the decrease in long-term potentiation (LTP) by varying the blast injury severity and the inter-blast interval between two blast exposures. LTP deficits were attenuated with increasing inter-blast intervals. We also investigated changes in microglial activation; expression of CD68 was increased and expression of CD206 was decreased after multiple blast exposures. Expression of macrophage inflammatory protein (MIP)-1α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1, interferon gamma-inducible protein (IP)-10, and regulated on activation, normal T cell expressed and secreted (RANTES) increased, while expression of IL-10 decreased in the acute period after both single and repeated bTBI. By partially depleting microglia prior to injury, LTP deficits after injury were significantly reduced. Treatment with the novel drug, MW-189, prevented LTP deficits when administered immediately following a repeated bTBI and even when administered only for an acute period (24 h) between two blast injuries. These findings could inform the development of therapeutic strategies to treat the neurological deficits of repeated bTBI suggesting that microglia play a major role in functional neuronal deficits and may be a viable therapeutic target to lessen the neurophysiological deficits after bTBI.

Postnatal GABAA Receptor Activation Alters Synaptic Plasticity and Cognition in Adult Wistar Rats.

Early life alteration in the activity of gamma-aminobutyric acid (GABA) receptors is associated with long-lasting developmental effects on the brain and behavior. GABAA receptors act as excitatory rather than inhibitory in neonates. Excessive activation of GABAA receptors during the early postnatal period may affect cognitive functions later in life. In this study, we sought to determine whether neonatal activation of GABAA receptors with muscimol can alter the electrophysiology profile of hippocampal CA1 neurons and spatial learning and memory in adult rats. Male and female Wistar rat pups received a subcutaneous injection of either saline or muscimol (500µg/kg) on postnatal days (PND) 7, 9, and 11 and then underwent different electrophysiology and behavioral experiments in adulthood. Early life treatment with muscimol did not alter the basic synaptic transmission but significantly reduced the paired-pulse facilitation (PPF) in the CA1 area. Neonatal application of muscimol led to a pronounced decrease in long-term potentiation (LTP) and long-term depression (LTD) in CA1 neurons along with a declined theta-burst responses in both sexes. We obtained some evidence that neonatal GABAA activation leads to reduced brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex. Our electrophysiology data was supported with spatial reference and working memory deficits in rats. This study provides the first detailed description of altered electrophysiology in hippocampal CA1 neurons in adult rats undergone GABAA activation early in life.

RAGE signaling is required for AMPA receptor dysfunction in the hippocampus of hyperglycemic mice

Diabetes in humans has been associated for a long time with cognitive dysfunction. In rodent animal models, cognitive dysfunction can manifest as impaired hippocampal synaptic plasticity. Particular attention has been concentrated on the receptor for advanced glycation end products (RAGE), which is implicated in multiple diabetic complications involving the development of vascular and peripheral nerve abnormalities. In this study, we hypothesize that RAGE signaling alters glutamate receptor function and expression, impairing synaptic transmission in the hippocampus. Using preparations of hippocampal slices from male mice, we show a RAGE-dependent decrease in long-term potentiation (LTP) and an increase in paired-pulse facilitation (PPF) following streptozotocin (STZ)-induced diabetes. Consistently, in hippocampal cultures from male and female neonatal mice, high glucose caused a RAGE-dependent reduction of AMPA- but not NMDA-evoked currents, and an increase in cytosolic reactive oxygen species (ROS). Consistently, when cultures were co-treated with high glucose and the RAGE antagonist FPS-ZM1, AMPA-evoked currents were unchanged. Hippocampi from STZ-induced hyperglycemic wild type (WT) mice showed increased RAGE expression concomitant with a decrease of both expression and phosphorylation (Ser 831 and 845) of the AMPA GluA1 subunit. We found these changes correlated to activation of the MAPK pathway, consistent with decreased pJNK/JNK ratio and the JNK kinase, pMEK7. As no changes in expression or phosphorylation of regulatory proteins were observed in hippocampi from STZ-induced hyperglycemic RAGE-KO mice, we report a RAGE-dependent impairment in the hippocampi of hyperglycemic WT mice, with reduced AMPA receptor expression/function and LTP deficits.

Physiology and Morphological Correlates of Excitatory Transmission are Preserved in Glutamine Transporter SN1-Depleted Mouse Frontal Cortex

Glutamine is an astroglia-derived precursor of the neurotransmitter glutamate, and its astroglia-to-neuron transfer is controlled by distinct glutamine transporters on the astrocytic and neuronal sites. In this study, we focused on the role of astrocytic glutamine efflux-mediating system N transporter SN1 in the maintenance of glutamatergic neurotransmission by analyzing the electrophysiological parameters ex vivo in the brain slices from control mice and mice in which vivo-morpholino technique was used to diminish SN1 protein. The glutamatergic transmission was characterized by electrophysiological recordings, ultrastructure of neuron terminals, and determination of proteins related to glutamate synaptic transmission: synaptophysin, synaptotagmin, and vit1A. The space-restricted ∼51,5% reduction of SN1 protein did not affect the expression of the neuronal glutamine transporter SAT2. SN1 depletion resulted in a reduction of field potentials (FPs), unaltered frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs), and presented a tendency towards a decrease of long-term potentiation (LTP). Ultrastructurally, preserved number of synaptic vesicles, primarily localized centrally of the cell body, correlates with unchanged levels of synaptic proteins. Collectively, the study indicates that glutamatergic transmission proceeds relatively independently of the SN1 - mediated glutamine transfer to the synapse.

Vestibular Modulation of Long-Term Potentiation and NMDA Receptor Expression in the Hippocampus.

Loss of vestibular function is known to cause spatial memory deficits and hippocampal dysfunction, in terms of impaired place cell firing and abnormal theta rhythm. Based on these results, it has been of interest to determine whether vestibular loss also affects the development and maintenance of long-term potentiation (LTP) in the hippocampus. This article summarizes and critically reviews the studies of hippocampal LTP following a vestibular loss and its relationship to NMDA receptor expression, that have been published to date. Although the available in vitro studies indicate that unilateral vestibular loss (UVL) results in reduced hippocampal field potentials in CA1 and the dentate gyrus (DG), the in vivo studies involving bilateral vestibular loss (BVL) do not. This may be due to the differences between UVL and BVL or it could be a result of in vitro/in vivo differences. One in vitro study reported a decrease in LTP in hippocampal slices following UVL; however, the two available in vivo studies have reported different results: either no effect or an increase in EPSP/Population Spike (ES) potentiation. This discrepancy may be due to the different high-frequency stimulation (HFS) paradigms used to induce LTP. The increased ES potentiation following BVL may be related to an increase in synaptic NMDA receptors, possibly increasing the flow of vestibular input coming into CA1, with a loss of selectivity. This might cause increased excitability and synaptic noise, which might lead to a degradation of spatial learning and memory.

Galantamine improves enhanced impulsivity, impairments of attention and long-term potentiation induced by prenatal nicotine exposure to mice

Prenatal nicotine exposure (PNE) causes behavioral abnormalities in offspring, such as an enhancement of impulsivity and decrease in attention at adolescence. Here we examined the effects of galantamine (GAL) on the behavioral and electrophysiological changes induced by PNE in mice. Pregnant C57BL/6J mice were exposed to nicotine (0.2 mg/mL) dissolved in sweetened (2% saccharin) drinking water during gestational day 14 and perinatal day 0 (P0). At the ages of postnatal days 42–49 (P42-P49), female offspring displayed impulsivity in the cliff avoidance test and impairment of visual attention in the object-based attention test. Decrease of long-term potentiation (LTP) and extracellular glutamate levels were observed in the prefrontal cortex of PNE mice. Systemic treatment with GAL (1 mg/kg, s.c.), an allosteric potentiating ligand for the nicotinic acetylcholine receptor (nAChR) and a weak cholinesterase inhibitor, attenuated the enhancement of impulsivity and impairment of attention induced by PNE in mice. Further, GAL reversed the impairment of LTP induced by PNE in the prefrontal cortex of mice, although it failed to attenuate the decrease of extracellular glutamate levels. The effects of GAL were blocked by an α 7 nAChR antagonist, methyllycaconitine (1 mg/kg, i.p.). These results suggest that PNE during cortex development affects nicotinic cholinergic-dependent plasticity and formation of impulsivity and attention. Furthermore, GAL could be a useful drug for cognitive impairments-related to attention deficit hyperactivity disorder.

Deficits in Motor Performance, Neurotransmitters and Synaptic Plasticity in Elderly and Experimental Parkinsonian Mice Lacking GPR37.

Parkinson’s disease (PD) etiology is attributed to aging and the progressive neurodegeneration of dopamine (DA) neurons of substantia nigra pars compacta (SNc). GPR37 is an orphan G-protein Coupled Receptor (GPCR) that is linked to the juvenile form of PD. In addition, misfolded GPR37 has been found in Lewy bodies. However, properly folded GPR37 found at the cell membrane appears to exert neuroprotection. In the present study we investigated the role of GPR37 in motor deficits due to aging or toxin-induced experimental parkinsonism. Elderly GPR37 knock out (KO) mice displayed hypolocomotion and worse fine movement performance compared to their WT counterparts. Striatal slice electrophysiology reveiled that GPR37 KO mice show profound decrease in long term potentiation (LTP) formation which is accompanied by an alteration in glutamate receptor subunit content. GPR37 KO animals exposed to intrastriatal 6-hydroxydopamine (6-OHDA) show poorer score in the behavioral cylinder test and more loss of the DA transporter (DAT) in striatum. The GPR37 KO striata exhibit a significant increase in GABA which is aggravated after DA depletion. Our data indicate that GPR37 KO mice have DA neuron deficit, enhanced striatal GABA levels and deficient corticostriatal LTP. They also respond stronger to 6-OHDA-induced neurotoxicity. Taken together, the data indicate that properly functional GPR37 may counteract aging processes and parkinsonism.

Involvement of homodomain interacting protein kinase 2-c-Jun N-terminal kinase/c-Jun cascade in the long-term synaptic toxicity and cognition impairment induced by neonatal Sevoflurane exposure.

Sevoflurane is one of the most widely used anesthetics with recent concerns rising about its pediatric application. The synaptic toxicity and mechanisms underlying its long‐term cognition impairment remain unclear. In this study, we investigated the expression and roles of homeodomain interacting protein kinase 2 (HIPK2), a stress activating kinase involved in neuronal survival and synaptic plasticity, and its downstream c‐Jun N‐terminal kinase (JNK)/c‐Jun signaling in the long‐term toxicity of neonatal Sevoflurane exposure. Our data showed that neonatal Sevoflurane exposure results in impairment of memory, enhancement of anxiety, less number of excitatory synapses and lower levels of synaptic proteins in the hippocampus of adult rats without significant changes of hippocampal neuron numbers. Up‐regulation of HIPK2 and JNK/c‐Jun was observed in hippocampal granular neurons shortly after Sevoflurane exposure and persisted to adult. 5‐((6‐Oxo‐5‐(6‐(piperazin‐1‐yl)pyridin‐3‐yl)‐1,6‐dihydropyridin‐3‐yl)methylene)thiazolidine‐2,4‐dione trifluoroacetate, antagonist of HIPK2, could significantly rescue the cognition impairment, decrease in long‐term potentiation, reduction in spine density and activation of JNK/c‐Jun induced by Sevoflurane. JNK antagonist SP600125 partially restored synapse development and cognitive function without affecting the expression of HIPK2. These data, in together, revealed a novel role of HIPK2‐JNK/c‐Jun signaling in the long‐term synaptic toxicity and cognition impairment of neonatal Sevoflurane exposure, indicating HIPK2‐JNK/c‐Jun cascade as a potential target for reducing the synaptic toxicity of Sevoflurane. Cover Image for this issue: doi: 10.1111/jnc.14757.

Cystatin C promotes cognitive dysfunction in rats with cerebral microbleeds by inhibiting the ERK/synapsin Ia/Ib pathway.

Although higher serum level of cystatin C (CysC) was observed in patients with cerebral microbleeds, its associated role in the disease has not been elucidated. In this work, a rat model of cerebral microbleeds was created with the aim of investigating effects of CysC on cognitive function in rats with cerebral microbleeds and the underlying mechanism. Serum samples of patients with cerebral microbleeds and healthy people of the same age were collected. Levels of cystatin C expression in these samples were measured using CysC kits. Moreover, 48 spontaneously hypertensive rats (SHRs) bred under specific pathogen-free (SPF) conditions were randomly divided into 4 groups: sham surgery control group (sham), model group (CMB), model + empty vector control group (CMB + vehicle), and model + cystatin C overexpression group (CMB + CysC). Expression levels of CysC in hippocampus of rats in each group were measured by western blot analysis. The Y-maze was used to evaluate cognitive function of rats. Hippocampal long-term potentiation (LTP) in rats was assessed by the electrophysiological assay. Alterations in levels of p-ERK1/2 and p-synapsin Ia/b proteins associated with cognitive function were identified by western blot analysis. The serum levels of CysC in patients with cerebral microbleeds were significantly upregulated (P<0.001). After injection of CysC, its expression levels in rat hippocampus were significantly increased (P<0.001), which enhanced the decline in learning and memory function, as well as the decrease of LTP in the rat model of cerebral microbleeds (P<0.001). Western blot results showed that injection of CysC further reduced the levels of p-ERK1/2 and p-synapsin Ia/b in the rat model of microbleeds (P<0.001). CysC was up regulated in serum of patients with cerebral microbleeds. It promoted cognitive dysfunction in rats with microbleeds by inhibiting ERK/synapsin Ia/Ib pathway.

Depletion of dietary phytoestrogens reduces hippocampal plasticity and contextual fear memory stability in adult male mouse

ABSTRACT Introduction: Phytoestrogens are non-steroidal estrogen analogues and are found primarily in soy products. They have received increasing attention as dietary supplements for estrogen deficiency and as modulators of endogenous estrogen functions, including cognition and emotion. In addition to modifying the levels of circulating sex hormones, phytoestrogens also exert direct effects on estrogen and androgen receptors in the brain and thus effectively modulate the neural circuit functions. Objective: The aim of this study was to investigate the long-term effects of low phytoestrogen intake (∼6 weeks) on the hippocampal plasticity and hippocampus-dependent memory formation in the adult C57BL/6 male mice. Methods and Results: In comparison to mice on a diet with normal phytoestrogen content, mice on low phytoestrogen diet showed a significant reduction in the phosphorylation of NR2B subunit, a molecular correlate of plasticity in the Schaffer collateral-CA1 synapse. We observed a profound decrease in long-term potentiation (LTP) in the ventral hippocampus, whereas no effect on plasticity was evident in its dorsal portion. Furthermore, we demonstrated that acute perfusion of slices with an estrogen analogue equol, an isoflovane metabolized from daidzein produced by the bacterial flora in the gut, was able to rescue the observed LTP deficit. Examining potential behavioral correlates of the plasticity attenuation, we found that mice on phytoestrogen-free diet display decreased contextual fear memory at remote but not at recent time points after training. Conclusions: Our data suggests that nutritional phytoestrogens have profound effects on the plasticity in the ventral hippocampus and ventral hippocampus-dependent memory.

Impairment of Long-term Memory by a Short-term High-fat Diet via Hippocampal Oxidative Stress and Alterations in Synaptic Plasticity

Excessive dietary fat intake is considered a great risk factor for metabolic disorders as well as cognitive dysfunction. However, the potential mechanisms underlying the effects of a high-fat diet (HFD) on the brain remain rather obscure. The purpose of this study was to address how early exposure to HFD induces biochemical changes in different brain regions and affects short- and long-term memory. Mice were fed HFD or normal chow for 4 or 7 weeks beginning in adulthood. Our results showed that oxidative stress and biochemical alterations first appeared in the hippocampus after 4 weeks of exposure and were aggravated by a longer exposure time. Additionally, the HFD-fed mice displayed long-term memory impairments, but the performance of the mice in both the HF-4W and HF-7W groups on behavioral tests relying on short-term memory was not affected. The effect of HFD on the brain was also assessed by electrophysiology, which detected a gradual decrease in long-term potentiation in the CA1 region of the hippocampus. The abnormal expression of proteins associated with synaptic function, e.g. synaptophysin, CaMKII, CaMKIV, calcineurin A, ERK and c-fos, was observed in the hippocampus in response to HFD. These results indicate that HFD elicits rapid biochemical and neurological abnormalities in the hippocampus that contribute to cognitive defects and are potentially connected to the HFD-induced suppression of brain activity.

Immediate and delayed decrease of long term potentiation and memory deficits after neonatal intermittent hypoxia

Apnea of prematurity is a common clinical condition that occurs in premature infants and results in intermittent hypoxia (IH) to brain and other organs. While short episodes of apnea are considered of no clinical significance, prolonged apnea with bradycardia and large oxygen desaturation is associated with adverse neurological and cognitive outcome. The mechanisms of cognitive deficits in IH are poorly understood. We hypothesized that brief but multiple episodes of severe oxygen desaturation accompanied by bradycardia may affect early and late synaptic plasticity and produce long-term cognitive deficits.C57BL/6 mouse pups were exposed to IH paradigm consisting of alternating cycles of 5% oxygen for 2.5 min and room air for 5–10 min, 2 h a day from P3 to P7. Long term potentiation (LTP) of synaptic strength in response to high frequency stimulation in hippocampal slices were examined 3 days and 6 weeks after IH. LTP was decreased in IH group relative to controls at both time points. That decrease was associated with deficits in spatial memory on Morris water maze and context fear conditioning test. Hypomyelination was observed in multiple gray and white matter areas on in vivo MRI using micromolecule proton fraction and ex vivo diffusion tensor imaging. No difference in caspase labeling was found between control and IH groups.We conclude that early changes in synaptic plasticity occurring during severe episodes of neonatal IH and persisting to adulthood may represent functional and structural substrate for long term cognitive deficits.

Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3×TgAD and 2×TgAD mice.

The triple transgenic mouse model (3×TgAD: APPswe, TauP301L, PS1M146V) recapitulates both amyloid β (Aβ)- and tau-related lesions as well as synaptic and memory deficits. In these mice, we reported an early apathy-like behavior and alterations in synaptic plasticity appearing concomitantly with intraneuronal accumulation of C99 in the subiculum. To delineate the genuine contribution of C99 on the above phenotypes, we generated double transgenic mice (2×TgAD: APPswe, TauP301L) that accumulate C99 without Aβ deposition or hyperphosphorylation of tau and compared them to 3×TgAD mice. Here, we show that both TgAD mice display similar decreases in long-term potentiation and in spontaneous locomotor activity measured by actimetry suggesting that the synaptic alterations and the apathy-like behavior were likely linked to C99 rather than Aβ. However, spatial learning alterations, assessed by the Morris water maze task, are more pronounced in 3×TgAD than in 2×TgAD, suggesting that both Aβ and C99 contribute to defects in the acquisition of spatial information. Finally, even if similar results are observed in males, cognitive and non-cognitive deficits are more severe in females.

Status Epilepticus Impairs Synaptic Plasticity in Rat Hippocampus and Is Followed by Changes in Expression of NMDA Receptors.

Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.

Interaction of Isoflurane, Tumor Necrosis Factor-α and β-Amyloid on Long-term Potentiation in Rat Hippocampal Slices.

The relationship between inhalational anesthetics such as isoflurane and cognitive impairment in the elderly is controversial. Both β-amyloid peptide (Aβ), associated with Alzheimer disease, and tumor necrosis factor-α (TNF-α), a proinflammatory stress-related peptide, impair the synaptic function. We hypothesized that transient exposure to isoflurane and these peptides would impair synaptic function, manifest as a depression of long-term potentiation (LTP) and paired pulse facilitation (PPF), in the rat hippocampus. Hippocampal slices were prepared from 3- to 4-week-old male Wistar rats. Preliminary experiments identified minimal concentrations of Aβ1-42 peptide and TNF-α that produced statistically detectable suppressing effects on LTP (600 nM Aβ1-42 and 5 ng/mL TNF-α). These concentrations of peptides were applied to slices alone, with 1.5% isoflurane, or in combination for 1 hour and then washed out. Measurements of LTP (field excitatory postsynaptic potentials [fEPSPs]) from neurons in the CA1 area by stimulation of the Schaffer-Collateral pathway were made after high-frequency stimulation (100 Hz, 1 second). Analysis of variance with correction for multiple comparisons was used to compare LTP under steady-state conditions and averaged for the 40- to 60-minute period after LTP induction. EPSP amplitude after LTP induction was 155% ± 9% of baseline and was not affected by isoflurane exposure and washout (150% ± 4% of baseline, P = .47). Both Aβ1-42 and TNF-α reduced LTP by approximately 15% compared with control (129% ± 7% and 131% ± 11% of baseline respectively, means ± SD, both P < .001). When Aβ1-42 was combined with isoflurane, LTP was not impaired (151% ± 9% of control, P = .85), but isoflurane had no effect on LTP depression caused by TNF-α or a combination of Aβ and TNF-α. Brief exposure to isoflurane prevents rather than impairs the decrease in LTP caused by Aβ1-42 in rat hippocampus. In contrast, isoflurane had no effect on synaptic impairment caused by TNF-α or a combination of TNF-α and Aβ. Although this is an in vitro study and translation to clinical medicine requires additional work, the interactions of isoflurane, Aβ, and TNF-α revealed here could have implications for patients with Alzheimer disease or perioperative neuroinflammation.

Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

Alpha-synuclein (αSyn) interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR) and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

Hypertension‐induced impairment in synaptic plasticity and dysregulation of genes involved in synaptic function in the mouse hippocampus: implications for the pathogenesis of vascular cognitive impairment in aging

Strong epidemiological and experimental evidence indicate that hypertension predisposes to cognitive decline in the elderly, but the underlying mechanisms remain elusive. Long‐term potentiation (LTP), defined as a long‐lasting increase in synaptic efficacy following high‐frequency stimulation of afferent fibers, is presumed to play an important role in the establishment and storage of memories in the hippocampus. The present study was designed to characterize the effects of hypertension on synaptic plasticity and the expression of genes involved in regulation of synaptic function in the hippocampus. Hypertension was induced in 3 and 24 month old C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. To determine whether hypertension compromises neuronal mechanisms of learning and memory, extracellular recordings were performed from acute hippocampal slices using multi‐electrode arrays. Field excitatory post‐synaptic potentials (fEPSPs) were invoked through stimulation of the performant path collaterals and obtained from the dentate gyrus area. We found that hypertension was associated with significant decreases in LTP, mimicking the aging phenotype. Synaptic density was decreased by hypertension, an effect that was exacerbated by aging. In aged mice hypertension decreased protein expression of NMDAR1 and NMDAR2A, whereas expression of GLUR1 and GLUR2 were unaffected. Hippocampal mRNA expression of genes involved in synaptic function was assessed using a targeted qPCR array. The hippocampal gene expression signature observed in hypertensive mice (including altered expression of Nptx2, Bdnf, Homer1, Stxbp1 (Munc‐18), Dlg4) provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer's disease.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on Aging

Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons

Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ∼50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period.