Inhibition Of Long-term Potentiation Research Articles

The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice.

GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)–dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABAARs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABAAR transport driven during NMDAR–dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABAARs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS–deficient neurons. This increase in surface GABAARs required the PX-RICS/GABARAP/14–3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced CaMKII–dependent phosphorylation of PX-RICS to promote PX-RICS–14-3-3 assembly. Notably, PX-RICS/RICS–deficient mice showed impaired amygdala–dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS–mediated GABAAR trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism.

Clitoria ternatea L. root extract ameliorated the cognitive and hippocampal long-term potentiation deficits induced by chronic cerebral hypoperfusion in the rat

Ethnopharmacological relevanceClitoria ternatea L. (CT), commonly known as Butterfly pea, is used in Indian Ayurvedic medicine to promote brain function and treat mental disorders. Root of CT has been proven to enhance memory, but its role in an animal model of chronic cerebral hypoperfusion (CCH), which has been considered as a major cause of brain disorders, has yet to be explored. Aim of the studyTo assess the motor and cognitive effects of acute oral administration of CT root methanolic extract and hippocampal long-term plasticity in the CA1 region of the CCH rat model. Materials and methodsMale Sprague Dawley rats (200–300 g) were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham operation. Then, these rats were given oral administration of CT root extract at doses of 100, 200 or 300 mg/kg on day 28 post-surgery and tested using behavioural tests (open-field test, passive avoidance task, and Morris water maze) and electrophysiological recordings (under urethane anaesthesia). ResultsTreatment with CT root extract at the doses of 200 and 300 mg/kg resulted in a significant enhancement in memory performance in CCH rats induced by PBOCCA. Furthermore, CCH resulted in inhibition of long-term potentiation (LTP) formation in the hippocampus, and CT root extract rescued the LTP impairment. The CT root extract was confirmed to improve the glutamate-induced calcium increase via calcium imaging using primary cultured rat neurons. No significance difference was found in the CaMKII expression. These results demonstrated that CT root extract ameliorates synaptic function, which may contribute to its improving effect on cognitive behaviour. ConclusionsOur findings demonstrated an improving effect of CT root extract on memory in the CCH rat model suggesting that CT root extract could be a potential therapeutic strategy to prevent the progression of cognitive deterioration in vascular dementia (VaD) and Alzheimer's disease (AD) patients.

MicroRNA-219 decreases hippocampal long-term potentiation inhibition and hippocampal neuronal cell apoptosis in type 2 diabetes mellitus mice by suppressing the NMDAR signaling pathway.

Type 2 diabetes mellitus (T2DM) is a complex polygenic disease that causes hyperglycemia and accounts for 90%-95% of all diabetes mellitus cases. Hence, this study aimed to examine the effects of microRNA-219 (miR-219) on inhibition of long-term potentiation (LTP) and apoptosis of hippocampal neuronal cells in T2DM mice through the N-methyl-d-aspartate receptor (NMDAR) signaling pathway regulation. The T2DM mouse models were established, after which LTP in vivo was recorded by means of electrical biology, and the fasting blood glucose of mice was measured. Next, the density of pyramidal neurons in each group was calculated. Additionally, the expression levels of miR-219, the NMDAR signaling pathway [NMDAR1 (NR) 1, NR2A, and NR2B), downstream target proteins [calmodulin-dependent protein kinase-II (CaMK-II) and cAMP response element binding protein (CREB)], and apoptosis-related factors [Bcl2-associated X protein (Bax), c-caspase-9 and c-caspase-3] in the hippocampal tissues were determined. Finally, immunohistochemistry was applied to detect and measure the positive expression of Bax, caspase-9, and caspase-3 proteins. The results showed that upregulation of miR-219 increases LTP and density of pyramidal neurons in the hippocampal tissues of mice, while it decreases blood glucose of db/db mice. In addition, miR-219 upregulation also leads to decreased mRNA levels of NR1, NR2A, NR2B, CaMK-II, and CREB and protein levels of NR1, NR2A, NR2B, CaMK-II, CREB, p-CREB, Bax, c-caspase-9, and c-caspase-3. Furthermore, upregulation of miR-219 inhibits positive expression of Bax, caspase-9, and caspase-3 proteins, leading to the suppression of hippocampal neuronal cell apoptosis. The findings from this study indicated that the upregulation of miR-219 decreases LTP inhibition and hippocampal neuronal cell apoptosis in T2DM mice by downregulating the NMDAR signaling pathway, therefore suggesting that MiR-219 might be a future therapeutic strategy for T2DM.

Reduced Cyclic Adenosine Monophosphate Level in Hippocampal CA1 Participates in Propofol Induced Amnesia in Rats.

Propofol inhibits long-term potentiation (LTP) in the hippocampal CA1 region and impedes episodic memory formation. However, the molecular mechanisms involved in the effect of propofol are still poorly understood. It had been reported that propofol inhibited cAMP response element binding protein signaling, which was proposed to contribute to memory retention impairment in rats. Here, we first demonstrated that propofol perfusion could inhibit forskolin induced LTP in the rat hippocampal CA1 slices. Propofol also reduced the level of cAMP, which could be reversed by non-selective PDE inhibitor IBMX. We further discovered that propofol could increase both PDE4 activity and PDE4AX protein expressions in the hippocampal CA1 region. Furthermore, pretreatment of rolipram, a PDE4 inhibitor, rescued propofol induced inhibition of CA1 LTP and the impairment of hippocampus-dependent memory formation in rats. Thus, our results suggest that reduced levels of cAMP by increasing PDE4 activity and PDE4AX protein expressions in the hippocampal CA1 region plays an important role in the propofol-induced amnesia.

Radiation induces age-dependent deficits in cortical synaptic plasticity.

Radiation-induced cognitive dysfunction is a significant side effect of cranial irradiation for brain tumors. Clinically, pediatric patients are more vulnerable than adults. However, the underlying mechanisms of dysfunction, including reasons for age dependence, are still largely unknown. Previous studies have focused on the loss of hippocampal neuronal precursor cells and deficits in memory. However, survivors may also experience deficits in attention, executive function, or other non-hippocampal-dependent cognitive domains. We hypothesized that brain irradiation induces age-dependent deficits in cortical synaptic plasticity. In vivo recordings were used to test neuronal plasticity along the direct pathway from the cornu ammonis 1 (CA1)/subicular region to the prefrontal cortex (PFC). Specifically, long-term potentiation (LTP) in the CA1/subicular-PFC pathway was assessed after cranial irradiation of juvenile and adult Sprague Dawley rats. We further assessed a potential role for glutamate toxicity by evaluating the potential neuroprotective effects of memantine. LTP was greatly inhibited in both adult and juvenile animals at 3 days after radiation but returned to near-normal levels by 8 weeks-only in adult rats. Memantine given before, but not after, irradiation partially prevented LTP inhibition in juvenile and adult rats. Cranial radiation impairs neuroplasticity along the hippocampal-PFC pathway; however, its effects vary by age. Pretreatment with memantine offered protection to both juvenile and adult animals. Deficits in cortical plasticity may contribute to radiation-induced cognitive dysfunction, including deficits in attention and age-dependent sensitivity of such pathways, which may underlie differences in clinical outcomes between juveniles and adults after cranial irradiation.

Glycinergic Inhibitory Plasticity in Binaural Neurons Is Cumulative and Gated by Developmental Changes in Action Potential Backpropagation

Utilization of timing-based sound localization cues by neurons in the medial superior olive (MSO) depends critically on glycinergic inhibitory inputs. After hearing onset, the strength and subcellular location of these inhibitory inputs are dramatically altered, but the cellular processes underlying this experience-dependent refinement are unknown. Here we reveal a form of inhibitory long-term potentiation (iLTP) in MSO neurons that is dependent on spiking and synaptic activation but is not affected by their fine-scale relative timing at higher frequencies prevalent in auditory circuits. We find that iLTP reinforces inhibitory inputs coactive with binaural excitation in acumulative manner, likely well suited for networks featuring persistent high-frequency activity. We also show that a steep drop in action potential size and backpropagation limits induction of iLTP to the first 2weeks of hearing. These intrinsic changes would deprive more distal inhibitory synapses of reinforcement, conceivably establishing the mature, soma-biased pattern of inhibition.

NGF steers microglia toward a neuroprotective phenotype.

Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti‐inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways. At the functional level, NGF induces an increase in membrane dynamics and macropinocytosis and, in vivo, it activates an outward rectifying current that appears to modulate glutamatergic neurotransmission in nearby neurons. Since microglia are supposed to be a major player in Aβ peptide clearance in the brain, we tested the effects of NGF on its phagocytosis. NGF was shown to promote TrkA‐mediated engulfment of Aβ by microglia, and to enhance its degradation. Additionally, the proinflammatory activation induced by Aβ treatment is counteracted by the concomitant administration of NGF. Moreover, by acting specifically on microglia, NGF protects neurons from the Aβ‐induced loss of dendritic spines and inhibition of long term potentiation. Finally, in an ex‐vivo setup of acute brain slices, we observed a similar increase in Aβ engulfment by microglial cells under the influence of NGF. Our work substantiates a role for NGF in the regulation of microglial homeostatic activities and points toward this neurotrophin as a neuroprotective agent in Aβ accumulation pathologies, via its anti‐inflammatory activity on microglia.

NLRP3-dependent synaptic plasticity deficit in an Alzheimer's disease amyloidosis model in vivo

Pro-inflammatory mechanisms have recently emerged as an important component of early Alzheimer's disease (AD) pathogenesis. A particularly attractive therapeutic strategy is to selectively prevent the disruptive effects of activation of the innate immune system in the brain at an early transitional stage by reducing the production or directly neutralizing pro-inflammatory cytokines, in particular IL-1β and TNF-α. Here we tested their in vivo effects on synaptic plasticity deficits, which provide sensitive and robust measures of synaptic failure, in a rat model of AD amyloidosis. Using electrophysiological techniques we longitudinally studied the effects of the NLRP3 inflammasome inhibitor Mcc950, the IL-1 receptor antagonist (anakinra) and an anti-TNF-α agent (etanercept) in awake freely moving transgenic rats overexpressing AD associated β-amyloid precursor protein at a pre-plaque stage of amyloidosis. Repeated treatment with Mcc950 reversibly abrogated the inhibition of long-term potentiation. The IL-1 receptor antagonist and etanercept also had a similar beneficial effect on the deficit in synaptic plasticity. Our findings support the clinical development of Mcc950 and clinically available IL-1- and TNF-α-neutralizing agents in early AD.

β-amyloid inhibits hippocampal LTP through TNFR/IKK/NF-κB pathway

ObjectiveThe suppressive action of the acute application of oligomeric amyloid-β (Aβ) on hippocampal long-term potentiation (LTP) has been reported widely. Many mechanisms have been proposed for Aβ inhibited LTP induction. The inflammatory cytokine tumor necrosis factor-α (TNF-α) has also been reported to play a key role in this LTP inhibition through Aβ. However, the underlying molecular mechanisms are largely unknown. This study aimed to investigate the link between Aβ- and TNF-α-mediated hippocampal LTP inhibition.MethodsAcute hippocampal slices of male wildtype or Alzheimer’s disease (AD) transgenic mouse models were treated with the inhibitors of either TNF-α, IκB Kinase (IKK) or Nuclear Factor-κB (NF-κB) in the presence or absence of oligomeric Aβ42 (500 nM/2 h). The LTP was assessed using field excitatory post synaptic potential recordings (fEPSP), and immunoblotting was used to evaluate the expression of IKK and NF-κB.ResultsAcute treatment with Aβ or TNF-α alone inhibited LTP and increased the phosphorylation of IKK and NF-κB in wild type mouse hippocampal slices. Pretreatment with TNF-α antagonist infliximab rescued the LTP impairment by Aβ and also restored the levels of IKK and NF-κB to the control levels. In addition, pretreatment with IKK2 IV or JSH23 also restored the Aβ-mediated LTP impairment. Furthermore, AD transgenic mouse hippocampal slices treated with infliximab or inhibitors of IKK or NF-κB showed improved LTP and reversed the activation of IKK and NF-κB.ConclusionIn conclusion, our observations suggest that the IKK/NF-κB signaling pathway play an important role in Aβ-mediated hippocampal LTP impairment. Aβ might modulate IKK/NF-κB activity by binding or activating tumor necrosis factor receptor (TNFR).

Cortical LTP: A Synaptic Model for Chronic Pain.

Cumulative evidence indicates that cortical synapses not only play important roles in pain perception and related emotional functions but also undergo long-term potentiation (LTP) and contribute to chronic pain. LTP is found at two key cortical regions such as the anterior cingulate cortex (ACC) and insular cortex (IC), and inhibition of cortical LTP produces analgesic effects as well as anxiolytic effects. In this chapter, I will summarize our work on ACC and IC and provide evidence for calcium-stimulated AC1 as a key molecule for cortical LTP and chronic pain.

Dual Influence of Endocannabinoids on Long-Term Potentiation of Synaptic Transmission.

Cannabinoid receptor 1 (CB1R) is widely distributed in the central nervous system, in excitatory and inhibitory neurons, and in astrocytes. CB1R agonists impair cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. Based on the knowledge that eCBs are released upon high frequency neuronal firing, we hypothesized that the influence of eCBs upon LTP could change according to the paradigm of LTP induction. We thus tested the influence of eCBs on hippocampal LTP using two θ-burst protocols that induce either a weak or a strong LTP. LTP induced by a weak-θ-burst protocol is facilitated while preventing the endogenous activation of CB1Rs. In contrast, the same procedures lead to inhibition of LTP induced by the strong-θ-burst protocol, suggestive of a facilitatory action of eCBs upon strong LTP. Accordingly, an inhibitor of the metabolism of the predominant eCB in the hippocampus, 2-arachidonoyl-glycerol (2-AG), facilitates strong LTP. The facilitatory action of endogenous CB1R activation does not require the activity of inhibitory A1 adenosine receptors, is not affected by inhibition of astrocytic metabolism, but involves inhibitory GABAergic transmission. The continuous activation of CB1Rs via exogenous cannabinoids, or by drugs known to prevent metabolism of the non-prevalent hippocampal eCB, anandamide, inhibited LTP. We conclude that endogenous activation of CB1Rs by physiologically formed eCBs exerts a fine-tune homeostatic control of LTP in the hippocampus, acting as a high-pass filter, therefore likely reducing the signal-to-noise ratio of synaptic strengthening.

Suppression of microRNA-9-5p rescues learning and memory in chronic cerebral hypoperfusion rats model.

Chronic cerebral hypoperfusion has been associated with cognitive impairment in dementias, such as Alzheimer's disease (AD) and vascular disease (VaD), the two most common neurodegenerative diseases in aged people. However, the effective therapeutic approaches for both AD and VaD are still missing. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in the epigenetic regulation in many neurological disorders; the critical roles of miRNAderegulation had been implicated in both AD and VaD. In the current study, we reported that miR-9-5p is elevated in the serum and cerebrospinalfluid of patientswith VaD. The miR-9-5p wasalso increased in both the hippocampus and cortex of rats with 2-vessel occlusionsurgery. Furthermore, application ofmiR-9-5p antagomirs attenuated the memory impairments in rats with 2-vessel occlusion surgery both in the Morris water maze and inhibitory avoidance step-down tasks. Furthermore, miR-9-5p antagomirs reducedthe inhibition oflong-term potentiation and loss of dendritic spines in chronic cerebral hypoperfusionrats. Additionally, the cholinergic neuronal function was rescued by miR-9-5p antagomirs, as well as the neuronal loss and the oxidative stress. We concluded that miR-9-5p inhibition may be a potential therapeutic target for the memory impairments caused by chronic cerebral hypoperfusion.

Near infrared light decreases synaptic vulnerability to amyloid beta oligomers

Synaptic dysfunction due to the disrupting binding of amyloid beta (Aβ) and tau oligomers is one of the earliest impairments in Alzheimer’s Disease (AD), driving initial cognitive deficits and clinical manifestation. Consequently, there is ample consensus that preventing early synaptic dysfunction would be an effective therapeutic strategy for AD. With this goal in mind, we investigated the effect of a treatment of mice with near infrared (NIR) light on synaptic vulnerability to Aβ oligomers. We found that Aβ oligomer binding to CNS synaptosomes isolated from wild type (wt) mice treated with NIR light was significantly reduced and the resulting suppression of long term potentiation (LTP) by Aβ oligomers was prevented. Similarly, APP transgenic mice treated with NIR showed a significant reduction of endogenous Aβ at CNS synapses. We further found that these phenomena were accompanied by increased synaptic mitochondrial membrane potential in both wt and Tg2576 mice. This study provides evidence that NIR light can effectively reduce synaptic vulnerability to damaging Aβ oligomers, thus furthering NIR light therapy as a viable treatment for AD.

Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity

Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABAA Receptors (GABAARs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABAAR clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABAAR clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

“Unpredictable Stress”: Ambiguity of Stress Reactivity in Studies of Long-Term Plasticity

Data on the influences of stress on the function of long-term synaptic plasticity are analyzed. Using longterm potentiation (LTP) as an example, stress has been shown to have both stimulatory and inhibitory influences on the effectiveness of the induction of long-term modifications, the effect depending on the nature, duration, and intensity of the stress, the observation time point, the brain structure being studied, and, thus, the involvement in the stress response of the different mechanisms underlying LTP. Stress-induced increases in glucocorticoid levels did not obligately correlate with changes in long-term plasticity, while application of corticosterone in vivo and in vitro could lead to both activation and inhibition of LTP. Existing data provide evidence that changes in LTP are determined by the ratio of mineralocorticoid and glucocorticoid receptors, activation of the latter not so much impairing the mechanisms of generation as increasing the threshold of induction of LTP, regulating the metaplasticity of synapses. The unpredictability of the effects of stress is related in particular to the involvement of other transmitter systems regulating metaplasticity whose actions depend on the animal’s individual experience in the stress reaction. The range of individual differences stimulates the ongoing search for significant factors determining the stress reactivity of longterm plasticity underlying stress resistance or susceptibility to its pathological consequences. Differences in the processing of signals arriving at neurons and their molecular mediation may constitute such a factor.

O41 Traditional Chinese medicine Liuwei Dihuang decoction and its new formula, LW-AFC, as promising therapies against Alzheimer’s disease: Pharmacological actions and mechanisms

Alzheimer’s disease (AD) is the leading cause of dementia that affects millions of elderly people worldwide. The currently available therapies have limited efficacy. Liuwei Dihuang decoction (LW), a classical traditional Chinese medicine (TCM) formula, has long been used to treat various diseases, including dementia. A large number of pharmacological studies have shown that LW has beneficial effects on AD. LW-AFC is a new formula consisting of the main active components prepared from LW. In this study, we found that administration of LW-AFC significantly improved behavioural performances in spontaneous locomotor activity, object recognition memory, spatial learning and memory, passive and active avoidance impairment in some AD mouse models, such as SAMP8 and APP/PS1 transgenic mice. Meanwhile, the impairments of long-term potentiation (LTP) were significantly ameliorated by LW-AFC administration in SAMP8 mice, as well as in the corticosterone-induced LTP inhibition mouse model. These effects were companied by an alleviation in neuron loss in the hippocampus, suppression of A-beta deposition in the brain, and a reduction in the concentration of Abeta42 in the hippocampus and plasma of APP/PS1 mice. The restoring and correcting of imbalance in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, the disorder of lymphocyte subsets, and the abnormalities in cytokine production were also observed in LW-AFC treated SAMP8 and APP/PS1 mice. These findings indicated that LW-AFC ameliorated the behavioural and pathological deterioration of AD mice via the restoration of the NIM network in a holistic way, suggesting that LW-AFC might be a promising therapy for AD.

Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice.

Alzheimer's disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-β protein (Aβ) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Aβ25-35-induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Aβ deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD.

Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease

Accumulation of amyloid β (Aβ) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aβ interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aβ-induced suppression of long term potentiation (LTP). Furthermore, specific ablation of ErbB4 in PV neurons via Cre/loxP system greatly improved spatial memory and synaptic plasticity in the hippocampus of hAPP-J20 mice. The deposition of Aβ detected by 3D6 and Thioflavin S staining and the proteolytic processing of hAPP analyzed by western blotting were not affected in the hippocampus of hAPP-J20 mice by deleting ErbB4 in PV neurons. Our data suggested that ErbB4 in PV neurons mediated Aβ-induced synaptic and cognitive dysfunctions without affecting Aβ levels.

Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau-/- mice.

Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human MAPT can restore Aβ-mediated inhibition on a mouse Tau−/− background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aβ-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full human MAPT locus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on a Tau−/− background. We found that the human wild-type MAPT H1 locus was able to restore Aβ42-mediated impairment of LTP. In contrast, Aβ42 did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD). Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that human MAPT is able to restore Aβ42-mediated inhibition of LTP in Tau−/− mice. These results provide further evidence that tau protein is central to Aβ-induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.

Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: Longitudinal studies

Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.