Irene Navarro-Lobato

Role of layer 6 of V2 visual cortex in object-recognition memory.

Modulating Visual Memory Layer 3 of the secondary visual cortical area V2 plays a role in visual information processing. However, in contrast to layer 3, layer 6 of visual cortex is composed of many types of neurons and their response to visual stimuli is more complex. The importance of layer 6 in visual information processing remains an enigma. López-Aranda et al. (p. 87; see the Perspective by Saksida) investigated its role in the rat visual cortex in the processing of both short- and long-term visual memory. Elimination of neurons from layer 6 of area V2 led to complete loss of normal memory. However, overexpression of a protein called RGS-14 in the same area boosted the visual memory capacity in such a way that the animals retained the visual information for many months, rather than the normal 45 minutes. Experiments reveal the localization of short- and long-term visual memory encoding in the rat visual cortex. Cellular responses in the V2 secondary visual cortex to simple as well as complex visual stimuli have been well studied. However, the role of area V2 in visual memory remains unexplored. We found that layer 6 neurons of V2 are crucial for the processing of object-recognition memory (ORM). Using the protein regulator of G protein signaling–14 (RGS-14) as a tool, we found that the expression of this protein into layer 6 neurons of rat-brain area V2 promoted the conversion of a normal short-term ORM that normally lasts for 45 minutes into long-term memory detectable even after many months. Furthermore, elimination of the same-layer neurons by means of injection of a selective cytotoxin resulted in the complete loss of normal as well as protein-mediated enhanced ORM.

Memory deficits in aging and neurological diseases.

Memory is central to our ability to perform daily life activities and correctly function in society. Improvements in public health and medical treatment for a variety of diseases have resulted in longer life spans; however, age-related memory impairments have been significant sources of morbidity. Loss in memory function is not only associated with aging population but is also a feature of neurodegenerative diseases such as Alzheimers disease and other psychiatric and neurological disorders. Here, we focus on current understanding of the impact of normal aging on memory and what is known about its mechanisms, and further review pathological mechanisms behind the cause of dementia in Alzheimers disease. Finally, we discuss schizophrenia and look into abnormalities in circuit function and neurotransmitter systems that contribute to memory impairment in this illness.

Activation of caspase-3 pathway by expression of sGαi2 protein in BHK cells

Treatment with dopamine and other dopamine D2 receptor agonists has been shown to induce cell death through activation of caspase-3 pathway. However, initial step that leads to the activation of caspase-3 in D2 receptor-mediated apoptotic pathway remains unclear. Recently, it was shown that a spliced variant of Galphai2 protein (sGalphai2) forms intracellular complex with D2 receptors by protein-protein interaction and that D2 drugs treatment causes the liberation of sGalphai2 protein from complex. Now, we show that the unbound form of sGalphai2 protein is able to activate caspase-3 pathway in baby hamster kidney (BHK) cells. Expression of sGalphai2 protein in BHK cells led to the production of active form of caspase-3 and activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular regulated kinase 1/2 (ERK1/2). Co-expression of sGalphai2 with either D2 short (D2S) or D2 long (D2L) isoforms of dopamine D2 receptors blocked the activation of caspase-3 pathway. Thus, our results demonstrate that high level of unbound sGalphai2 protein can affect the cell survival and engagement of this protein with D2 receptors can block this process. It is suggested that this process may be a crucial step in the initiation of D2 receptor-mediated cellular apoptosis through this pathway.

RGS-14(414) gene delivery into brain area V2 induces both the recovery and prevention of recognition memory in ageing and Alzheimer's disease

neurogenesis and maturation of newly generated neurons in the brain of subjects with AD and delay or prevent the progression of the disease is stimulation of endogenous neurotrophic factors. Neurotrophic factors a family of structurally related, secreted proteins, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), ciliary neurotrophic factor (CNTF), NT-3, and NT4/5, are small proteins that provide trophic events in neuronal cells. These secreted neurotrophic factors act by binding to the specific cell surface receptors that signal the neuron to survive. Methods: Neurotrophic factors are important in the developing and mature nervous system. They influence cell proliferation, survival, differentiation, migration, axon and dendritic growth and synaptic plasticity. They play critical roles in complex behaviors including anxiety, depression and learning. They can be given exogenously as pure proteins or through gene therapy to prevent nerve cell death caused by various insults including nerve injury, brain trauma, and exposure to toxins. Results: The high potency of neurotrophic factors, as shown by many experimental studies, makes them a rational candidate therapeutic agent in neurodegenerative disease. Because the administration of exogenous neurotrophic factors is time consuming and expensive for the most of patients and also it needs to gene delivery, intense care considerations and probably it’s side effects, therefore it seems that the manipulation of endogenous neurotrophic factors is suitable treatment for AD.Conclusions: It is concluded that the manipulation and stimulation of endogenous neurotrophic factors is a promising therapeutic strategy in Alzheimer’s disease.

A correlation of haloperidol-induced cognitive deficit with dysfunctional dopamine receptor activity in nonhuman primate

Haloperidol is an antipsychotic drug that acts through blockage of dopamine D 2 receptors. Chronic administration of this antipsychotic drug in nonhuman primates induces a pronounced cognitive deficit. However, receptor subtypes that are responsible for this cogni - tive dysfunction remain unknown. Therefore, brains of chronic haloperidol-treated young and aged monkeys were used to analyze the intricate relation of receptor activity, cognitive dysfunction, and haloperidol-mediated actions in the production of harmful effects. Tak- ing into account the significant cognitive loss observed after haloperidol treatment, it was predicted that changes in the cognitive status that correlate with the receptor activity in the prefrontal cortex and striatum, areas implicated in the processing of haloperidol-mediated effects in brain, should be common in both young and aged animals. Based on this concept, we observed that in the prefrontal cortex, dopamine D 1 and D 2 receptors showed changes in receptor levels that were common in both age groups. However, this relationship was absent in GABA A , serotonin 5HT2 and muscaranic receptors. In contrast to the prefrontal cortex, in striatum, this change was restricted to the dopamine D 2 receptors only. Therefore, from our results, it seems that apart from the downregulation of D 1 receptor activity in the prefrontal cortex, an upregulation of D 2 receptors could also contribute to the generation of the cognitive loss observed in haloperidol-treated monkeys. Additionally, reduced excitatory input due to hampered cortico-striatal D 1 dopaminergic activity and stronger inhibition at the synapse of excitatory input site by upregulated striatal D 2 receptor activity could promote the side effects

A dynamic expression pattern of sGαi2 protein during early period of postnatal rat brain development

The function of sGαi2 protein in central nervous system is not well understood. Therefore to explore the possible role of this protein in postnatal brain development, we have analyzed the protein expression pattern of brain obtained from rats of postnatal day 0 (P0) to P90 by dot‐blots and immunocytochemistry techniques. In dot‐blots, both nuclear and membrane fractions showed a gradual decrease from P0 to P60. Highest protein level was observed at the age of P0. There was also a trend of decline in the sGαi2 protein from P0 to P90 in brain sections stained by immunocytochemistry method. At P0, the protein labeling was highest in cerebral cortex, hippocampus, cerebellum and mitral cell layer. In cerebral cortex, a drop in the immunolabeling of sGαi2 protein was observed at P3, which was significantly increased at the age of P5. However, in striatum and olfactory tubercle, it was maintained through P0–P10 and P0–P5, respectively. Thalamus was one of the areas where labeling was not as strong as cortex, hippocampus or striatum. In contrary to other areas, immunostaining of sGαi2 in corpus‐callosum and lacunosum‐moleculare was not seen at P0 and appeared in advanced postnatal ages. A detectable level of sGαi2 protein was observed at P5 in carpus‐callosum and at P20 in lacunosum‐moleculare. A high level of sGαi2 protein in the period when cellular layer organization and synaptic innervations, synaptic connections and maturation take place, suggests for a potential role of this protein in the early postnatal brain development.