eIF2α controls memory consolidation via excitatory and somatostatin neurons.

An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1-4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5-10. One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF211. Phosphorylation of the α-subunit of eIF2 (p-eIF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds11-13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14-17, or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease18. Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.

Discrepancies of Notch 1 receptor during development of chronic seizures.

The critical role of Notch signaling has been shown in the pathogenesis of some neurological disorders including schizophrenia, epilepsy and Alzheimer's disease. This study was aimed to evaluate the role of Notch 1 receptor in epileptogenesis as well as seizure characteristics. The animals were divided into three groups of sham, early stage and end stage. In sham group: Normal saline was injected intraperitoneally (ip) in the same as protocol of pentylenetetrazol (PTZ) injection. PTZ was injected (ip) every 48 hr over a period of 1 week in the group of early stage and over a period of 4 weeks in the end stage. The gene expression as well as distribution of Notch 1 receptor was assessed in the parietal cortex and hippocampus. In addition, the effect of agonist or antagonist of Notch 1 receptor was assessed on the epileptic discharges induced by PTZ injection. The gene expression of Notch 1 decreased in the hippocampus significantly in the end-stage group compared with sham, and early groups. Furthermore, distribution of Notch 1 receptor increased in the somatosensory cortex and decreased in the CA1 hippocampal area in the end-stage group. Intraventricular microinjection of Notch 1 agonist significantly increased the amplitude as well as frequency of spikes and decreased the latency of first epileptic discharges. Our findings illustrate the critical role of Notch signalling as a potential pathway in the epileptogenesis during development of chronic seizures.

Impaired Memory and Evidence of Histopathology in CA1 Pyramidal Neurons through Injection of Aß1-42 Peptides into the Frontal Cortices of Rat.

INTRODUCTION: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which has much benefited from animal models to find the basics of its pathophysiology. In our previous work (Haghani, Shabani, Javan, Motamedi, & Janahmadi, 2012), a non-transgenic rat model of AD was used in electrophysiological studies. However, we did not investigate the histological aspects in the mentioned study. METHODS: An AD model was developed through bilateral injection of amyloid-ß peptides (Aß) into the frontal cortices. Behavioral and histological methods were used to assess alterations in the memory and (ultra)structures. Furthermore, melatonin has been administered to assess its efficacy on this AD model. RESULTS: Passive avoidance showed a progressive decline in the memory following Aß injection. Furthermore, Nissl staining showed that Aß neurotoxicity caused shrinkage of the CA1 pyramidal neurons. Neurodegeneration was clearly evident from Fluoro-jade labeled neurons in Aß treated rats. Moreover, higher NF-κB immunoreactive CA1 pyramidal neurons were remarkably observed in Aß treated rats. Ultrastructural analysis using electron microscopy also showed the evidence of subcellular abnormalities. Melatonin treatment in this model of AD prevented Aß-induced increased NF-κB from immunoreaction and neurodegeneration. DISCUSSION: This study suggests that injection of Aß into the frontal cortices results in the memory decline and histochemical disturbances in CA1 pyramidal neurons. Furthermore, melatonin can prevent several histological changes induced by Aß.

Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain.

Temporal lobe epilepsy is often presented by medically intractable recurrent seizures due to dysfunction of temporal lobe structures, mostly the temporomesial structures. The role of transient receptor potential vaniloid 1 (TRPV1) activity on synaptic plasticity of the epileptic brain tissues was investigated. We studied hippocampal TRPV1 protein content and distribution in the hippocampus of epileptic rats. Furthermore, the effects of pharmacologic modulation of TRPV1 receptors on field excitatory postsynaptic potentials have been analyzed after induction of long term potentiation (LTP) in the hippocampal CA1 and CA3 areas after 1 day (acute phase) and 3 months (chronic phase) of pilocarpine-induced status epilepticus (SE). A higher expression of TRPV1 protein in the hippocampus as well as a higher distribution of this channel in CA1 and CA3 areas in both acute and chronic phases of pilocarpine-induced SE was observed. Activation of TRPV1 using capsaicin (1 µM) enhanced LTP induction in CA1 region in non-epileptic rats. Inhibition of TRPV1 by capsazepine (10 µM) did not affect LTP induction in non-epileptic rats. In acute phase of SE, activation of TRPV1 enhanced LTP in both CA1 and CA3 areas but TRPV1 inhibition did not affect LTP. In chronic phase of SE, application of TRPV1 antagonist enhanced LTP induction in CA1 and CA3 regions but TRPV1 activation had no effect on LTP. These findings indicate that a higher expression of TRPV1 in epileptic conditions is accompanied by a functional impact on the synaptic plasticity in the hippocampus. This suggests TRPV1 as a potential target in treatment of seizure attacks.