A similar phenomenon has been observed in schizophrenia, both in animal models (Nullmeier et al., 2011) and patients (Akbarian et al., 1995; Impagnatiello et al., 1998; Guidotti et al., 2000; Hashimoto et al., 2003; Lewis et al., 2005). In conclusion, this study reveals early alterations in hippocampal neuronal phenotypes that are associated with a functional increase in oscillatory activity and precede A accumulation. are critically involved in the control of hippocampal theta oscillations, we then assessed intrinsic theta oscillations in these regions after a 4-aminopyridine (4AP) challenge. This revealed increased theta power and populace bursts in TgCRND8 mice compared to non-transgenic (nTg) controls, suggesting a hyperexcitability network state. Taken together, our results identify for the first time AD-related alterations in hippocampal interneuron function as early as at 1 month of age. These early functional alterations occurring before amyloid deposition may contribute to cognitive dysfunction in AD. treatment of 1 Pitavastatin Lactone 1.5C2 month-old TgCRND8 mice with pentylenetetrazole, a drug that inhibits type-A -aminobutyric acid (GABA) receptors (Del Vecchio et al., 2004). This may be due to the AD-related decrease in parvalbumin (PV) neuron activation, which leads to hyperexcitability (Verret et al., 2012). More recently, using the same AD model, we have reported that delicate alterations in synchronization of intrinsic hippocampal gamma and theta oscillations are detected as early as 1 month of age in TgCRND8 mice (Goutagny et al., 2013). Given that hippocampal network activity is usually coordinated by GABAergic neurons (Cobb et Pitavastatin Lactone al., 1995; Lawrence and McBain, 2003; Mann and Paulsen, 2007; Amilhon et al., 2015), GABAergic neuronal dysfunction may lead to network over-excitation, and thus underlie an increased susceptibility to seizures. Similarly, soluble A can disrupt excitatory-inhibitory balance, a specific AD-linked (apoE4) genotype has been associated with impairment of GABAergic interneurons, and GABAergic activation-induced hyperpolarization prevents A-related toxicity (Huang and Mucke, 2012; Paula-Lima et al., 2013; Nava-Mesa et al., 2014). However, the dysfunction of GABAergic interneurons in the earliest AD-associated state of hippocampal excitability and network synchronization has not been assessed. Here, we investigated putative GABAergic interneuronal impairment in 1 month-old TgCRND8 mice. A pathology progresses during the course of aging, and 6 month-old TgCRND8 mice have high levels of A and severe plaque load in many brain regions, including the hippocampus (Chishti et al., 2001). Although A plaques are undetectable before 3 months of age (Chishti et al., 2001), CTF, the first cleavage Pitavastatin Lactone product of APP is usually expressed already at 1 month (Cavanagh et al., 2013; Goutagny et al., 2013). Impaired overall performance in cognitive tasks is usually first detectable at 2 months of age, but only when more sensitive assessments such as object recognition tasks are used, as 2 month-old TgCRND8 mice are unimpaired on a Morris water maze task (Francis et al., 2012). We chose to examine TgCRND8 mice at 1 month of age because it corresponds to the AD pathogenesis stage at which alterations in hippocampal neuronal activity may be first detectable, as no difference has been detected between 15 days-old TgCRND8 mice and control littermates (Goutagny et al., 2013). We focused on neuropeptide Y (NPY; Palop et al., 2011) and PV (Verret et al., 2012) hippocampal interneurons, as both subtypes have been shown to be particularly affected in AD. Moreover, NPY and PV interneurons are critically involved in the control of hippocampal excitability (Palop et al., 2007) and network synchronization (Verret et al., 2012; Amilhon et al., 2015), respectively. CLTB Materials and Methods Animals All experiments followed the guidelines and guidelines of the Canadian Council on Animal Care and the animal care regulations Pitavastatin Lactone of McGill University or college. TgCRND8 mice bear Swedish KM670/671NL and Indiana V717F mutations in the hAAPP-encoding gene and overexpress human A by 3C4 months. Male TgCRND8 and non-transgenic (nTg) mice were maintained on an outbred C3H/C57BL6 background and kept on a 12 h light/dark cycle with food and water = 8 mice) were dissected on ice, snap frozen and stored at ?80C until proteins were extracted. Hippocampus samples were homogenized in radioimmunoprecipitation assay (RIPA) buffer (100 l per hippocampus) and left on ice for 30 min. The samples were then centrifuged for 10 min at 1000 g at 4C. The supernatants were collected and protein concentrations were decided using a BCA assay kit (Pierce, Rockford, IL, USA). The CTF content was then assessed in triplicates using an ELISA kit (IBL International, Japan) as per manufacturers instructions. Briefly, samples were diluted in enzyme immunoassay (EIA) buffer (1:100) and requirements were prepared as directed. 100 l of each sample was loaded into the appropriate wells and incubated immediately at 4C. The plate was then washed seven occasions using diluted wash buffer. One hundred microliter of labeled antibody answer was loaded into each well, and the plate was.