Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy, which involves enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a cellular mechanism for fear extinction; however, a direct link between depotentiation and extinction has not yet been tested. To address this issue, we applied both ex vivo and in vivo approaches to rats in which fear memory had been consolidated. A unique form of depotentiation reversed conditioning-induced potentiation at thalamic input synapses onto the LA (T-LA synapses) ex vivo. Extinction returned the enhanced T-LA synaptic efficacy observed in conditioned rats to baseline and occluded the depotentiation. Consistently, extinction reversed conditioning-induced enhancement of surface expression of AMPAR subunits in LA synaptosomal preparations. A GluR2-derived peptide that blocks regulated AMPAR endocytosis inhibited depotentiation, and microinjection of a cell-permeable form of the peptide into the LA attenuated extinction. Our results are consistent with the use of depotentiation to weaken potentiated synaptic inputs onto the LA during extinction and provide strong evidence that AMPAR removal at excitatory synapses in the LA underlies extinction.lateral amygdala ͉ fear conditioning ͉ AMPA receptor ͉ endocytosis T he cortical and thalamic input synapses onto the lateral amygdala (LA) (C-LA and T-LA synapses, respectively) carry auditory information from the auditory cortex and auditory thalamus onto the LA, respectively (1). Long-term potentiation (LTP; an in vitro model of memory) (2)-like changes in these pathways are thought to underlie both the encoding and consolidation of auditory fear memory (3-8). The results of a recent study suggest that long-term retention of conditioning-induced potentiation at excitatory synapses in the LA is a critical requirement for consolidated fear memory within the LA (7, 9). Also, LTP requiring the synaptic delivery of AMPA receptors (AMPARs) at excitatory synapses in the LA appears to be necessary for establishing consolidated fear memory (6,8,10). Conditioning-induced potentiation and auditory fear memory encoded in the LA have been shown to be consolidated within 24 h after fear conditioning (5, 7, 11). Moreover, auditory fear memory appears to be maintained in the LA across the adult lifetime of rats (12). Thus, consolidation of auditory fear memory encoded in the LA is rapid and localized, unlike hippocampus-dependent memory, which involves slow and distributed consolidation processes (13).In the present study, we tested the hypothesis that depotentiation of conditioning-induced potentiation at excitatory synapses in the LA underlies extinction of consolidated fear memory. Synaptic weights were monitored ex vivo by using whole-cell (or field potential) recordings in amygdala slices prepared from behaviortrained rats. Results Extinction of Consolidated ...

Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca 2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.A lzheimer´s disease (AD) is the most common cause of dementia globally, with an increasing impact on aging societies (1). Therefore, the prevention and treatment of AD is a major unmet medical need. The amyloid hypothesis posits that the abnormal accumulation of amyloid-β (Aβ) peptides in the brain, and their aggregation, is an essential feature of AD (2, 3); however, results from clinical studies using several Aβ-targeting compounds have called into question the existence of a direct link between a reduction in Aβ and improvement of brain function, particularly in more advanced disease stages (4-6). In addition, recent evidence obtained in mouse models carrying genetic mutations that cause AD in humans revealed that immunotherapy with antibodies against Aβ worsened rather than reversed neuronal dysfunction (7). Despite reducing plaque burden, the anti-Aβ antibodies caused a massive increase in cortical hyperactivity and promoted abnormal synchrony of neurons in a subset of the treated mice. In this context, it is noteworthy that another recent mouse study found an increased risk of sudden death after anti-Aβ antibody treatment, which was attributed to enhanced excitatory neuronal activity culminating in fatal convulsive seizures (8).To clarify the causal relationship between Aβ and pathophysiology in vivo, we made use of a novel compound that reduces Aβ by inhibiting the β-secretase BACE, the rate-limiting enzyme for Aβ production (9). This approach allowed us to determine how the inhibition of Aβ production affects neural circuit and memory impairments in APP23xPS45 transgenic mice overexpressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1). The combination of histochemistry, in vivo Ca 2+ imaging, and behavioral analysis allowed us to directly link the treatment-related changes in brain Aβ levels to changes in neuronal and cognitive functions in individual mice. ResultsIn this study, we used 6-to 8-mo-old APP23xPS45 transgenic mice that exhibit severe cerebral Aβ pathology, neur...

Among the most promising approaches for treating Alzheimer's disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies.

The amygdala is known to be a critical storage site of conditioned fear memory. Among the two major pathways to the lateral amygdala (LA), the cortical pathway is known to display a presynaptic long-term potentiation which is occluded with fear conditioning. Here we show that fear extinction results in a net depression of conditioning-induced potentiation at cortical input synapses onto the LA (C-LA synapses). Fear conditioning induced a significant potentiation of excitatory postsynaptic currents at C-LA synapses compared with naïve and unpaired controls, whereas extinction apparently reversed this potentiation. Paired-pulse low-frequency stimulation (pp-LFS) induced synaptic depression in the C-LA pathway of fear-conditioned rats, but not in naïve or unpaired controls, indicating that the pp-LFS-induced depression is specific to associative learning-induced changes (pp-LFS-induced depotentiation(ex vivo)). Importantly, extinction occluded pp-LFS-induced depotentiation(ex vivo), suggesting that extinction shares some mechanisms with the depotentiation. pp-LFS-induced depotentiation(ex vivo) required NMDA receptor (NMDAR) activity, consistent with a previous finding that blockade of amygdala NMDARs impaired fear extinction. In addition, pp-LFS-induced depotentiation(ex vivo) required activity of group II metabotropic glutamate receptors (mGluRs), known to be present at presynaptic terminals, but not AMPAR internalization, consistent with a presynaptic mechanism for pp-LFS-induced depotentiation(ex vivo). This result is in contrast with another form of ex vivo depotentiation in the thalamic pathway that requires both group I mGluR activity and AMPAR internalization. We thus suggest that extinction of conditioned fear involves a distinct form of depotentiation at C-LA synapses, which depends upon both NMDARs and group II mGluRs.

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