Ketamine modulates spontaneous and miniature excitatory synaptic currents in the medial prefrontal cortex of acutely stressed rats

The cellular and functional changes underlying the adaptive or maladaptive behavioral effects of an acute stressor are not well understood. In the medial prefrontal cortex (mPFC) of preclinical animal models, an acute stressor may rapidly change dendritic morphology and synaptic function. In the male rat mPFC, the foot-shock stress protocol (FS) rapidly (\uf07e1 hr) increases the number of excitatory synapses, the readily releasable Glu vesicle pool, [K+]-evoked Glu release from synaptosomes (doi.org/10.3389/fpsyt.2015.00060), and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) recorded in L2/3 pyramidal neurons (Pyr). Within 24 hrs, FS induces shrinkage of apical dendrites, while no information exists for sEPSCs. Miniature excitatory synaptic currents (mEPSCs) have been suggested to have a neurotrophic and homeostatic role, but the effects of FS on mEPSCs are unknown. To understand the sustained effects of FS on Glu transmission in the mPFC and its regulation by ketamine at antidepressant dosage, synaptic currents were recorded 24 hrs after FS in visually identified layer 2/3 Pyr of prelimbic mPFC in slices from adult male rats. Animals subjected to a 40-min session of inescapable FS (FS group), animals injected with ketamine (10mg/kg) 6 hrs after FS, and controls (CTR) were compared. The amplitude, area, rise, decay, and inter-event intervals of mEPSCs and sEPSCs were analyzed. mEPSCs in the FS group showed minor changes in frequency (small increase) and ampitude (small decrease) vs CTR. Ketamine after FS increased mEPSC frequency and peak amplitude and accelerated rise and decay with no change in area, vs CTR. The above effects were significant with the Kolmogorov-Smirnov test on pooled cumulative unbinned data but not with 2-way ANOVA of binned histograms. sEPSCs frequency in the FS group had a small decrease, with no change in waveform vs. CTR. Ketamine after FS produced similar effects on sESPCs as for mEPSCs. Overall, this work indicates that, 24 hrs after FS, minor changes occur in miniature and spontaneous synaptic currents at layer 2/3 Glu synapses of the mPFC of adult male rats. Ketamine effects on Glu synaptic currents of stressed animals suggest changes in synapse morphology and/or dendritic localization

Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor

We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron-sulfur (Fe-S) and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared with CT neurons, indicating deficient Fe-S cluster biogenesis, altered iron metabolism, and oxidative stress. Treatment with the benzamide HDAC inhibitor 109 significantly upregulated FXN expression and increased Fe-S and lipoic acid-containing protein levels, downregulated SOD2 levels, normalized LIP and ROS levels, and almost fully protected FRDA neurons from oxidative stress-mediated cell death. Our findings suggest that correction of FXN deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of na\uefve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites

Mortality rate and risk factors for gastrointestinal bleeding in elderly patients

Background: Gastrointestinal bleeding (GIB) is burdened by high mortality rate that increases with aging. Elderly patients may be exposed to multiple risk factors for GIB. We aimed at defining the impact of GIB in elderly patients.Methods: Since 2008, samples of elderly patients (age >= 65 years) with multimorbidity admitted to 101 internal medicine wards across Italy have been prospectively enrolled and followed-up (REPOSI registry). Diagnoses of GIB, length of stay (LOS), mortality rate, and possible risk factors, including drugs, index of comorbidity (Cumulative Illness Rating Scale [CIRS]), polypharmacy, and chronic diseases were assessed. Adjusted multivariate logistic regression models were computed.Results: 3872 patients were included (mean age 79 +/- 7.5 years, F:M ratio 1.1:1). GIB was reported in 120 patients (mean age 79.6 +/- 7.3 years, F:M 0.9:1), with a crude prevalence of 3.1%. Upper GIB occurred in 72 patients (mean age 79.3 +/- 7.6 years, F:M 0.8:1), lower GIB in 51 patients (mean age 79.4 +/- 7.1 years, F:M 0.9:1), and both upper/lower GIB in 3 patients. Hemorrhagic gastritis/duodenitis and colonic diverticular disease were the most common causes. The LOS of patients with GIB was 11.7 +/- 8.1 days, with a 3.3% in-hospital and a 9.4% 3-month mortality rates. Liver cirrhosis (OR 5.64; CI 2.51-12.65), non-ASA antiplatelet agents (OR 2.70; CI 1.23-5.90), and CIRS index of comorbidity > 3 (OR 2.41; CI 1.16-4.98) were associated with GIB (p < 0.05).Conclusions: A high index of comorbidity is associated with high odds of GIB in elderly patients. The use of non-ASA antiplatelet agents should be discussed in patients with multimorbidity