Conformational signaling required for synaptic plasticity by the NMDA receptor complex

The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.Agonist binding to the NMDAR is required for two major forms of synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD) (1). Surprisingly, activation of NMDARs can produce plasticity in opposite directions, with LTP enhancing transmission and LTD reducing transmission. A model was developed (2, 3) to explain how activation of NMDAR could produce these opposing phenomena: strong stimuli during LTP induction drive a large flux of Ca²⁺ through NMDARs, leading to a large increase in intracellular calcium ion concentration ([Ca²⁺]_i) that activates one series of biochemical steps leading to synaptic potentiation; a weaker stimulus during LTD induction drives a more reduced flux of Ca²⁺ through NMDARs, producing a modest increase in [Ca²⁺]_i that activates a different series of biochemical steps, leading to synaptic depression. However, this model is not consistent with recent studies suggesting that no change in [Ca²⁺]_i is required for LTD, and instead invokes metabotropic signaling by the NMDAR (4). Studies supporting an ion-flow-independent role for NMDARs in LTD (4–7) and other processes (7–13) stand in contrast to studies proposing that flow of Ca²⁺ through NMDAR is required for LTD (14) (see ref. 15 for additional references). An important test of an ion-flow-independent model would be to measure directly signaling actions by NMDARs in the absence of ion flow.     

BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment

Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain‐derived neurotrophic factor (BDNF) supports hippocampal long‐term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus‐dependent learning that occurs following EE. In the absence of EE, LTP elicited by high‐frequency stimulation was equivalent in wildtype mice and heterozygous BDNF^+/? siblings. LTP elicited by theta‐burst stimulation in BDNF^+/? mice was less than in wildtypes. Long‐term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF^+/? mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Adolescent brain maturation,the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia

Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose–time–effect relationship should be central.     

N-ethylmaleimide-sensitive factor is required for the synaptic incorporation and removal of AMPA receptors during cerebellar long-term depression

Cerebellar long-term depression (LTD) is a persistent attenuation of synaptic transmission at the parallel fiber-Purkinje cell synapse mediated by the removal of GluR2 subunit-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The removal of AMPA receptors requires protein kinase C phosphorylation of the GluR2 subunit within its carboxyl-terminal PSD-95/Discs Large/Zona Occludens-1 (PDZ) ligand and binding of the PDZ domain-containing protein, PICK1. The sequence of the GluR2 subunit is similar to that of the GluR3 and GluR4c subunits, which also contain PDZ ligands and protein kinase C consensus sites. Although GluR3 and GluR4c are also expressed in Purkinje cells, we have previously shown that cerebellar LTD is absent in GluR2(-/-) mice, suggesting that these subunits are unable to substitute functionally for GluR2. Here, we examine the apparent difference in the regulation of these AMPA receptor subunits by attempting to rescue LTD in GluR2(-/-) Purkinje cells with WT and mutant GluR2 and GluR3 subunits. Our results show that the selective interaction of the GluR2 subunit with the N-ethylmaleimide-sensitive factor protein is required for synaptic, but not extrasynaptic, incorporation of AMPA receptors as well as for their competence to undergo LTD. In addition, perfusion of a synthetic peptide that acutely disrupts the interaction of GluR2 with N-ethylmaleimide-sensitive factor selectively depletes GluR2-containing receptors from synapses and occludes LTD. These findings demonstrate that interaction of AMPA receptors with N-ethylmaleimide-sensitive factor plays a critical role in incorporation of AMPA receptors into synapses and for their subsequent removal during cerebellar LTD.     

Foot disorders in the elderly: A mini-review

Ageing process is associated with changes to the aspect, biomechanics, structure and function of the foot, it may be related with a marked presence of foot conditions, pain, disability and other overall health problems that constitute a major public health concern.Also, the prevalence of epidemiologic research found an incidence of foot problems which is even higher as a consequence of increasing life expectation. Several studies have also suggested that such foot disorders currently affect between 71 and 87% of older patients and are a frequent cause of medical and foot care.Thus, these kind problems are extremely common conditions in the general population, especially in the elderly who are associated with poor quality of life, balance impairment, increase the risk of falls, dificulty on putting shoes, fractures, restrict mobility and performance of activities of daily living that turn can produce serious physical, mental and social consequences in the older people.The role of the physician in the assessment, evaluation, and examination of foot problems is very important, yet it is often an overlooked and undervalued component of geriatric health care.The purpose of this article is to review and to provide an overview of the most common foot deformities precipitating factors, clinical presentation, evidence-based diagnostic evaluation, and treatment recommendations with a view to preventing medical conditions or deformities affecting the feet that may alter foot condition and general health amongst the elderly.     

Estrogen synthesis in the brain—Role in synaptic plasticity and memory

Estrogen and androgen are synthesized from cholesterol locally in hippocampal neurons of adult animals. These neurosteroids are synthesized by cytochrome P450s and hydroxysteroid dehydrogenases (HSDs) and 5alpha-reductase. The expression levels of enzymes are as low as 1/200–1/50,000 of those in endocrine organs, however these numbers are high enough for local synthesis. Localization of P450(17alpha), P450arom, 17beta-HSD and 5alpha-reductase is observed in principal glutamatergic neurons in CA1, CA3 and the dendate gyrus. Several nanomolar levels of estrogen and androgen are observed in the hippocampus.Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. Rapid action of 17beta-estradiol via membrane receptors is demonstrated for spinogenesis and long-term depression (LTD). The enhancement of LTD by 1–10 nM estradiol occurs within 1 h. The density of spine is increased in CA1 pyramidal neurons within 2 h after application of estradiol. The density of spine-like structure is, however, decreased by estradiol in CA3 pyramidal neurons. ERalpha, but not ERbeta, induces the same enhancement/suppression effects on both spinogenesis and LTD.     

Sleep and hippocampus: Do we search for the right things?

In addition to its established function in brain restoration, energy saving, circadian homeostasis, thermoregulation, and ontogenetic brain development, sleep is involved in replay and restructuring of memory representations that may lead to memory consolidation. The degree of availability of these memory-related functions in various species, and in disparate environmental and behavioral situations is widely debated. Generally it seems that species which can afford to sleep deeply show an involvement of sleep in learning and memory, both, hippocampus-dependent and hippocampus-independent. Inconsistencies in the sleep literature concerning the importance of certain sleep states for learning of various tasks and the involvement of different types of memory do not disprove that sleep plays a role in memory consolidation. In this review, we attempt to reconcile some of the seemingly antagonistic theories of sleep function in a succinct and unbiased manner and develop an eclectic view of its role in learning and memory.     

Metabotropic glutamate receptor dependent long-term depression in the cortex

Metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), a type of synaptic plasticity, is characterized by a reduction in the synaptic response, mainly at the excitatory synapses of the neurons. The hippocampus and the cerebellum have been the most extensively studied regions in mGluR-dependent LTD, and Group 1 mGluR has been reported to be mainly involved in this synaptic LTD at excitatory synapses. However, mGluR-dependent LTD in other brain regions may be involved in the specific behaviors or diseases. In this paper, we focus on five cortical regions and review the literature that implicates their contribution to the pathogenesis of several behaviors and specific conditions associated with mGluR-dependent LTD.