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Why layers II/III of entorhinal cortex (EC) deteriorate in advance of other regions during the earliest stages of Alzheimer's disease is poorly understood. Failure of retrograde trophic support from synapses to cell bodies is a common cause of neuronal atrophy, and we accordingly tested for early-life deterioration in projections of rodent layer II EC neurons. Using electrophysiology and quantitative imaging, changes in EC terminals during young adulthood were evaluated in male rats and mice. Field excitatory postsynaptic potentials, input/output curves, and frequency following capacity by lateral perforant path (LPP) projections from lateral EC to dentate gyrus were unchanged from 3 to 8-10 months of age. In contrast, the unusual presynaptic form of long-term potentiation (LTP) expressed by the LPP was profoundly impaired by 8 months in rats and mice. This impairment was accompanied by a reduction in the spine to terminal endocannabinoid signaling needed for LPP-LTP induction and was offset by an agent that enhances signaling. There was a pronounced age-related increase in synaptophysin within LPP terminals, an effect suggestive of incipient pathology. Relatedly, presynaptic levels of TrkB-receptors mediating retrograde trophic signaling-were reduced in the LPP terminal field. LTP and TrkB content were also reduced in the medial perforant path of 8- to 10-month-old rats. As predicted, performance on an LPP-dependent episodic memory task declined by late adulthood. We propose that memory-related synaptic plasticity in EC projections is unusually sensitive to aging, which predisposes EC neurons to pathogenesis later in life.SIGNIFICANCE STATEMENT Neurons within human superficial entorhinal cortex are particularly vulnerable to effects of aging and Alzheimer's disease, although why this is the case is not understood. Here we report that perforant path projections from layer II entorhinal cortex to the dentate gyrus exhibit rapid aging in rodents, including reduced synaptic plasticity and abnormal protein content by 8-10 months of age. Moreover, there was a substantial decline in the performance of an episodic memory task that depends on entorhinal cortical projections at the same ages. Overall, the results suggest that the loss of plasticity and related trophic signaling predispose the entorhinal neurons to functional decline in relatively young adulthood.

Rationale: Considerable clinical and experimental studies have shown that depression-related disorders are the most common neuropsychiatric symptoms in Alzheimer's disease (AD), affecting as many as 20–40% of patients. An increasing amount of evidence shows that monoamine-based antidepressant treatments are not completely effective for depression treatment in patients with dementia. Minocycline, a second-generation tetracycline antibiotic, has been gaining research and clinical attention for the treatment of different neuropsychiatric disorders, and more recently depression symptom in humans. Methods: In the present study, we investigated the effects of Aβ1–42 administration alone or in combination with minocycline treatment on depression-like behaviors and anti/pro-inflammatory cytokines such as interleukin(IL)-10, IL-β, and tumor necrosis factor (TNF)-α in the hippocampus of rats. Results: Our results showed that Aβ1–42 administration increased depression-related behaviors in sucrose preference test, tail suspension test, novelty-suppressed feeding test, and forced swim test. We also found significant increases in IL-1β and TNF-α levels in the hippocampus of Aβ1–42-treated rats. Interestingly, minocycline treatment significantly reversed depression-related behaviors and the levels of hippocampal cytokines in Aβ1–42-treated rats. Conclusion: These findings support the idea that there is a significant relationship among AD, depression-related symptoms, and pro-inflammatory cytokines in the brain, and suggest that antidepressant-like impacts of minocycline could be due to its anti-inflammatory properties. This drug could be of potential interest for the treatment of depression in patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Highlights • Intracerebroventricular (i.c.v.) injection of okadaic acid (OKA) drastically attenuates fEPSP slope and population spike in hippocampal DG neurons. • Intracerebroventricular injection of OKA significantly decreases the short-term and long-term synaptic plasticity of hippocampal DG neurons. • Administration of OKA results in impaired short-term and long-term spatial memories in rats. Abstract Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) have a critical effect on various regulatory mechanisms involved in synaptic plasticity, learning and memory. Okadaic acid (OKA), a potent inhibitor of PP1 and PP2A, reportedly leads to cognitive decline and Alzheimer's disease (AD)-like pathology. The aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons in vivo. Male Wistar rats were divided into two control and OKA groups. OKA was injected intracerebroventricularly (i.c.v.) into lateral ventricles and after two weeks the long-term potentiation (LTP) and paired-pulse responses recorded from hippocampal perforant path-DG synapses in order to assess short-term and long-term synaptic plasticity. Results of this study revealed that OKA-induced inhibition of PP1 and PP2A activity drastically attenuates the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude following paired pulse and high frequency stimulation (HFS) of hippocampal DG neurons indicating pre- and post-synaptic involvement in electrical activity of these neurons. Administration of OKA impaired the short-term and long-term spatial memories conducted by Y-maze and passive avoidance tests, respectively. OKA-induced attenuation in electrophysiological activity and consequent memory deficits also provide a beneficial tool for studying neurodegenerative disorders such as AD. [ABSTRACT FROM AUTHOR]

Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the β-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 μl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future. [ABSTRACT FROM AUTHOR]