Visual recognition memory: a view from V1

Although work in primates on higher-order visual areas has revealed how the individual and concerted activity of neurons correlates with behavioral reports of object recognition, very little is known about the underlying mechanisms for visual recognition memory. Low-level vision, even as early as primary visual cortex (V1) and even in subjects as unsophisticated as rodents, promises to fill this void. Although this latter approach sacrifices interrogation of many of the most astounding features of visual recognition, it does provide experimental constraint, proximity to sensory input, and a wide range of interventional approaches. The tractability of rodent visual cortex promises to reveal the molecular mechanisms and circuits that are essential for a fundamental form of memory.National Eye Institute (Grant RO1EY023037

NMDA Induces Long-Term Synaptic Depression and Dephosphorylation of the GluR1 Subunit of AMPA Receptors in Hippocampus

AbstractBrief bath application of N-methyl-D-aspartate (NMDA) to hippocampal slices produces long-term synaptic depression (LTD) in CA1 that is (1) sensitive to postnatal age, (2) saturable, (3) induced postsynaptically, (4) reversible, and (5) not associated with a change in paired pulse facilitation. Chemically induced LTD (Chem-LTD) and homosynaptic LTD are mutually occluding, suggesting a common expression mechanism. Using phosphorylation site–specific antibodies, we found that induction of chem-LTD produces a persistent dephosphorylation of the GluR1 subunit of AMPA receptors at serine 845, a cAMP-dependent protein kinase (PKA) substrate, but not at serine 831, a substrate of protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). These results suggest that dephosphorylation of AMPA receptors is an expression mechanism for LTD and indicate an unexpected role of PKA in the postsynaptic modulation of excitatory synaptic transmission

Recovery From Monocular Deprivation Using Binocular Deprivation: Experimental Observations and Theoretical Analysis

Ocular dominance (OD) plasticity is a robust paradigm for examining the functional consequences of synaptic plasticity. Previous experimental and theoretical results have shown that OD plasticity can be accounted for by known synaptic plasticity mechanisms, using the assumption that deprivation by lid suture eliminates spatial structure in the deprived channel. Here we show that in the mouse, recovery from monocular lid suture can be obtained by subsequent binocular lid suture but not by dark rearing. This poses a significant challenge to previous theoretical results. We therefore performed simulations with a natural input environment appropriate for mouse visual cortex. In contrast to previous work we assume that lid suture causes degradation but not elimination of spatial structure, whereas dark rearing produces elimination of spatial structure. We present experimental evidence that supports this assumption, measuring responses through sutured lids in the mouse. The change in assumptions about the input environment is sufficient to account for new experimental observations, while still accounting for previous experimental results

Cannabinoid Receptor Blockade Reveals Parallel Plasticity Mechanisms in Different Layers of Mouse Visual Cortex

SummaryThe ocular dominance (OD) shift that occurs in visual cortex after brief monocular deprivation (MD) is a classic model of experience-dependent cortical plasticity. It has been suggested that OD plasticity in layer 2/3 of visual cortex precedes and is necessary for plasticity in the thalamocortical input layer 4. Here, we show in mouse visual cortex that rapid OD plasticity occurs simultaneously in layers 2/3 and 4. Remarkably, pharmacological blockade of cannabinoid receptors completely prevents the OD shift in layer 2/3, leaving plasticity intact in layer 4. Thus, experience-dependent cortical modifications in layers 2/3 and 4 can occur in parallel, via distinct mechanisms. These findings simplify the mechanistic description of plasticity in layer 4, force a revision in the interpretation of previous studies in which laminar differences in OD plasticity mechanisms were unrecognized, and have important implications for the therapeutic use of cannabinoid receptor antagonists in humans

Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex

As in other mammals with binocular vision, monocular lid suture in mice induces bidirectional plasticity: rapid weakening of responses evoked through the deprived eye followed by delayed strengthening of responses through the open eye. It has been proposed that these bidirectional changes occur through three distinct processes: first, deprived-eye responses rapidly weaken through homosynaptic long-term depression (LTD); second, as the period of deprivation progresses, the modification threshold determining the boundary between synaptic depression and synaptic potentiation becomes lower, favouring potentiation; and third, facilitated by the decreased modification threshold, open-eye responses are strengthened via homosynaptic long-term potentiation (LTP). Of these processes, deprived-eye depression has received the greatest attention, and although several alternative hypotheses are also supported by current research, evidence suggests that α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor endocytosis through LTD is a key mechanism. The change in modification threshold appears to occur partly through changes in N-methyl-d-aspartate (NMDA) receptor subunit composition, with decreases in the ratio of NR2A to NR2B facilitating potentiation. Although limited research has directly addressed the question of open-eye potentiation, several studies suggest that LTP could account for observed changes in vivo. This review will discuss evidence supporting this three-stage model, along with outstanding issues in the field

Toward Fulfilling the Promise of Molecular Medicine in Fragile X

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.)National Institute of Mental Health (U.S.)FRAXA Research Foundatio

Obligatory Role of NR2A for Metaplasticity in Visual Cortex

Light deprivation lowers the threshold for long-term depression (LTD) and long-term potentiation (LTP) in visual cortex by a process termed metaplasticity, but the mechanism is unknown. The decreased LTD/P threshold correlates with a decrease in the ratio of NR2A to NR2B subunits of cortical NMDA receptors (NMDARs) and a slowing of NMDAR-mediated excitatory postsynaptic currents (EPSCs). However, whether and how changes in NR2 subunit expression contribute to LTD and LTP remains controversial. In the present study, we used an NR2A knockout (KO) mouse to examine the role of this subunit in the experience-dependent modulation of NMDAR properties, LTD, and LTP. In wild-type (WT) mice, we found what has previously been shown in rats, that dark rearing alters NMDAR EPSC kinetics and temporal summation, LTP, and LTD in layer 2/3 of visual cortex. Deletion of NR2A mimicked the effect of dark-rearing on NMDAR EPSCs, and there was no additional effect of dark-rearing in the NR2A KO mice. Thus, deletion of NR2A abrogates the effects of visual experience on NMDAR EPSCs. Moreover, metaplasticity of LTP and LTD was completely lost in the absence of NR2A. These data support the hypothesis that experience-dependent changes in NR2A/B are functionally significant and yield a mechanism for an adjustable synaptic modification threshold in visual cortex

Chemically treated 3D printed polymer scaffolds for biomineral formation

We present the synthesis of nylon-12 scaffolds by 3D printing and demonstrate their versatility as matrices for cell growth, differentiation, and biomineral formation. We demonstrate that the porous nature of the printed parts makes them ideal for the direct incorporation of preformed nanomaterials or material precursors, leading to nanocomposites with very different properties and environments for cell growth. Additives such as those derived from sources such as tetraethyl orthosilicate applied at a low temperature promote successful cell growth, due partly to the high surface area of the porous matrix. The incorporation of presynthesized iron oxide nanoparticles led to a material that showed rapid heating in response to an applied ac magnetic field, an excellent property for use in gene expression and, with further improvement, chemical-free sterilization. These methods also avoid changing polymer feedstocks and contaminating or even damaging commonly used selective laser sintering printers. The chemically treated 3D printed matrices presented herein have great potential for use in addressing current issues surrounding bone grafting, implants, and skeletal repair, and a wide variety of possible incorporated material combinations could impact many other areas