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Biomedical subjects

Alcino J Silva

Publications and source records attributed to Alcino J Silva.

At least 19 recordsLinked to original sources
PubMed2006

Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory.

Matrix metalloproteinases (MMPs) are extracellular proteases that have well recognized roles in cell signaling and remodeling in many tissues. In the brain, their activation and function are customarily associated with injury or pathology. Here, we demonstrate a novel role for MMP-9 in hippocampal synaptic physiology, plasticity, and memory. MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late-phase long-term potentiation (L-LTP) in area CA1. Such regulation requires NMDA receptors and protein synthesis. Blockade of MMP-9 pharmacologically prevents induction of L-LTP selectively; MMP-9 plays no role in, nor is regulated during, other forms of short-term synaptic potentiation or long-lasting synaptic depression. Similarly, in slices from MMP-9 null-mutant mice, hippocampal LTP, but not long-term depression, is impaired in magnitude and duration; adding recombinant active MMP-9 to null-mutant slices restores the magnitude and duration of LTP to wild-type levels. Activated MMP-9 localizes in part to synapses and modulates hippocampal synaptic physiology through integrin receptors, because integrin function-blocking reagents prevent an MMP-9-mediated potentiation of synaptic signal strength. The fundamental importance of MMP-9 function in modulating hippocampal synaptic physiology and plasticity is underscored by behavioral impairments in hippocampal-dependent memory displayed by MMP-9 null-mutant mice. Together, these data reveal new functions for MMPs in synaptic and behavioral plasticity.

Animals↗
PubMed2006

Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory.

Raf kinases are downstream effectors of Ras and upstream activators of the MEK-ERK cascade. Ras and MEK-ERK signaling play roles in learning and memory (L&M) and neural plasticity, but the roles of Raf kinases in L&M and plasticity are unclear. Among Raf isoforms, B-raf is preferentially expressed in the brain. To determine whether B-raf has a role in synaptic plasticity and L&M, we used the Cre-LoxP gene targeting system to derive forebrain excitatory neuron B-raf knockout mice. This conditional knockout resulted in deficits in ERK activation and hippocampal long-term potentiation (LTP) and impairments in hippocampus-dependent L&M, including spatial learning and contextual discrimination. Despite the widespread expression of B-raf, this mutation did not disrupt other forms of L&M, such as cued fear conditioning and conditioned taste aversion. Our findings demonstrate that B-raf plays a role in hippocampal ERK activation, synaptic plasticity, and L&M.

Animals↗
PubMed2006

Neurofibromatosis type 1: new insights into neurocognitive issues.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder with a prevalence of approximately 1 in 3500 people. Academic difficulties and school failure are the most common reported complication of NF1 in childhood and are present in 40% to 60% of the cases. They are often the most significant cause of lifetime morbidity in this population. Recent advances in the recognition and characterization of the cognitive phenotype in NF1 patients have provided a better understanding of the neuropsychologic deficits that account for the impairments in cognitive performance and social interaction. Additionally, recent advances in the understanding of molecular and cellular mechanisms underlying the cognitive deficits in NF1, as well as developments in neuroimaging and molecular genetic techniques are starting to yield a global and integrative picture of the molecular, cellular, and brain system processes affected by this condition. This review focuses on these advances, as well as recent preclinical studies that point towards potential pharmacologic interventions for NF1 patients.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Investigation of age-related cognitive decline using mice as a model system: neurophysiological correlates.

OBJECTIVE: Learning and memory impairments without overt pathology often accompany advancing age. To gain a better understanding of the underlying neuronal substrates associated with this age-related cognitive decline, the authors have begun to use mice as an animal model system. As described in the companion paper, mice exhibit age-related impairments in cognition. Here, the authors explore the possibility that age-related changes in neuronal function may be the result of deregulation of cytosolic free calcium homeostasis. METHODS: Calcium homeostasis in young and aged mice was examined by measuring the slow afterhyperpolarization (sAHP) in hippocampal neurons as well as assessing voltage-dependent calcium channel mediated long-term potentiation (vdccLTP). In addition, putative changes in phosphorylation of the L-type channel Ca(V)1.2 by cAMP-dependent protein kinase were examined. RESULTS: Both neurophysiological measures of calcium homeostasis indicated an increase in activity-dependent calcium influx. This increase was not the result of an age-related increase in phosphorylation of the L-type channel Ca(V)1.2 by cAMP-dependent protein kinase. CONCLUSIONS: Like in other areas of biomedical research, mice have become an invaluable research tool in the investigation of learning and memory. It is expected that similar benefits can be realized by developing mouse models for age-related cognitive decline.

2-Amino-5-phosphonovalerate↗
PubMed2006

Investigation of age-related cognitive decline using mice as a model system: behavioral correlates.

OBJECTIVE: With recent advances in molecular genetics, mouse models have been generated for a number of disease states. Recently, the authors and others have begun to examine normal age-related cognitive decline using mice as a model system. In this article, and the companion article that follows, the authors present data intended to better parameterize the aging phenotype in mice and examine the possible underlying neuronal mechanisms with special emphasis on age-related changes in calcium homeostasis. METHODS: Young (4-6-month-old) and aged (22-24-month-old) C57BL/6 mice were analyzed in terms of their spatial learning abilities in the hidden platform version of the Morris water maze and the delay win-shift version of the Olton radial arm maze. RESULTS: Although aged mice exhibited cognitive impairments in both behavioral tasks used, the extent of impairment differed between the two tasks, which might prove to be advantageous under certain experimental settings. CONCLUSIONS: Like in other areas of biomedical research, mice have become an invaluable research tool in the investigation of learning and memory. It is expected that similar benefits can be realized by developing mouse models for age-related cognitive decline.

Aging↗
PubMed2006

Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.

Alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)), we studied the role of alphaCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus-dependent spatial learning in the Morris water maze. Wild-type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild-type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning-specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, alphaCaMKII(T286A) mice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild-type controls after water-maze training. Notably, both trained and swim-control groups of alphaCaMKII(T286A) mutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal alphaCaMKII function. This result demonstrates dissociation of alphaCaMKII-independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitability per se are not perfectly correlated with learning. Our findings suggest that alphaCaMKII signaling may function to suppress learning-unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.

Action Potentials↗
PubMed2005

The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP). Importantly, NF1 causes learning disabilities and attention deficits. A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1+/-) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP), a cellular mechanism of learning and memory. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity in the brain. Lovastatin is a specific inhibitor of three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used commonly for the treatment of hypercholesterolemia. We report that lovastatin decreased the enhanced brain p21Ras-MAPK activity of the nf1+/- mice, rescued their LTP deficits, and reversed their spatial learning and attention impairments. Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1.

Analysis of Variance↗
PubMed2005

Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway.

Molecular and cellular studies of the mechanisms underlying mammalian learning and memory have focused almost exclusively on postsynaptic function. We now reveal an experience-dependent presynaptic mechanism that modulates learning and synaptic plasticity in mice. Consistent with a presynaptic function for endogenous H-ras/extracellular signal-regulated kinase (ERK) signaling, we observed that, under normal physiologic conditions in wild-type mice, hippocampus-dependent learning stimulated the ERK-dependent phosphorylation of synapsin I, and MEK (MAP kinase kinase)/ERK inhibition selectively decreased the frequency of miniature EPSCs. By generating transgenic mice expressing a constitutively active form of H-ras (H-rasG12V), which is abundantly localized in axon terminals, we were able to increase the ERK-dependent phosphorylation of synapsin I. This resulted in several presynaptic changes, including a higher density of docked neurotransmitter vesicles in glutamatergic terminals, an increased frequency of miniature EPSCs, and increased paired-pulse facilitation. In addition, we observed facilitated neurotransmitter release selectively during high-frequency activity with consequent increases in long-term potentiation. Moreover, these mice showed dramatic enhancements in hippocampus-dependent learning. Importantly, deletion of synapsin I, an exclusively presynaptic protein, blocked the enhancements of learning, presynaptic plasticity, and long-term potentiation. Together with previous invertebrate studies, these results demonstrate that presynaptic plasticity represents an important evolutionarily conserved mechanism for modulating learning and memory.

Animals↗
PubMed2005

Trace eyeblink conditioning requires the hippocampus but not autophosphorylation of alphaCaMKII in mice.

Little is known about signaling mechanisms underlying temporal associative learning. Here, we show that mice with a targeted point mutation that prevents autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)) learn trace eyeblink conditioning normally. This forms a sharp contrast to the severely impaired spatial learning in the water maze and contextual fear conditioning observed in alphaCaMKII(T286A) mutants. Importantly, hippocampal lesions impaired trace eyeblink conditioning in alphaCaMKII(T286A) mice, suggesting a potential role of hippocampal alphaCaMKII-independent mechanisms. These results indicate that hippocampal signaling mechanisms that underlie temporal associative learning as assessed by trace eyeblink conditioning may differ from those of spatial and contextual learning.

Animals↗
PubMed2005

Notch to remember.

Some of the signaling molecules required for formation of long-term memories are involved primarily in adult brain function, but others participate in a variety of other biological processes. The Notch signaling pathway, which is important for cell fate specification and differentiation in various systems, is also active in the mature brain. Here, we review evidence from recent studies indicating that Notch signaling is required for formation of long-term memories, and discuss possible memory processes modulated by this pathway. We also consider the possible involvement of Notch signaling in cognitive disorders.

Animals↗
PubMed2004

Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice.

BACKGROUND: Advancing age is typically accompanied by deficits in learning and memory. These deficits occur independently of overt pathology and are often considered to be a part of "normal aging." At the neuronal level, normal aging is known to be associated with numerous cellular and molecular changes, which include a pronounced decrease in neuronal excitability and an altered induction in the threshold for synaptic plasticity. Because both of these mechanisms (neuronal excitability and synaptic plasticity) have been implicated as putative cellular substrates for learning and memory, it is reasonable to propose that age-related changes in these mechanisms may contribute to the general cognitive decline that occurs during aging. RESULTS: To further investigate the relationship between aging, learning and memory, neuronal excitability, and synaptic plasticity, we have carried out experiments with aged mice that lack the auxiliary potassium channel subunit Kvbeta1.1. In aged mice, the deletion of the auxiliary potassium channel subunit Kvbeta1.1 resulted in increased neuronal excitability, as measured by a decrease in the post-burst afterhyperpolarization. In addition, long-term potentiation (LTP) was more readily induced in aged Kvbeta1.1 knockout mice. Finally, the aged Kvbeta1.1 mutants outperformed age-matched controls in the hidden-platform version of the Morris water maze. Interestingly, the enhancements in excitability and learning were both sensitive to genetic background: The enhanced learning was only observed in a genetic background in which the mutants exhibited increased neuronal excitability. CONCLUSIONS: Neuronal excitability is an important determinant of both synaptic plasticity and learning in aged subjects.

Action Potentials↗
PubMed2004

New circuits for old memories: the role of the neocortex in consolidation.

Studies of learning and memory have provided a great deal of evidence implicating hippocampal mechanisms in the initial storage of facts and events. However, until recently, there were few hints as to how and where this information was permanently stored. A recent series of rodent molecular and cellular cognition studies provide compelling evidence for the involvement of specific neocortical regions in the storage of information initially processed in the hippocampus. Areas of the prefrontal cortex, including the anterior cingulate and prelimbic cortices, and the temporal cortex show robust increases in activity specifically following remote memory retrieval. Importantly, damage to or inactivation of these areas produces selective remote memory deficits. Additionally, transgenic studies provide glimpses into the molecular and cellular mechanisms underlying cortical memory consolidation. The studies reviewed here represent the first exciting steps toward the understanding of the molecular, cellular, and systems mechanisms of how the brain stores our oldest and perhaps most defining memories.

Animals↗
PubMed2004

Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction.

Delta-catenin (delta-catenin) is a neuron-specific catenin, which has been implicated in adhesion and dendritic branching. Moreover, deletions of delta-catenin correlate with the severity of mental retardation in Cri-du-Chat syndrome (CDCS), which may account for 1% of all mentally retarded individuals. Interestingly, delta-catenin was first identified through its interaction with Presenilin-1 (PS1), the molecule most frequently mutated in familial Alzheimer's Disease (FAD). We investigated whether deletion of delta-catenin would be sufficient to cause cognitive dysfunction by generating mice with a targeted mutation of the delta-catenin gene (delta-cat(-/-)). We observed that delta-cat(-/-) animals are viable and have severe impairments in cognitive function. Furthermore, mutant mice display a range of abnormalities in hippocampal short-term and long-term synaptic plasticity. Also, N-cadherin and PSD-95, two proteins that interact with delta-catenin, are significantly reduced in mutant mice. These deficits are severe but specific because delta-cat(-/-) mice display a variety of normal behaviors, exhibit normal baseline synaptic transmission, and have normal levels of the synaptic adherens proteins E-cadherin and beta-catenin. These data reveal a critical role for delta-catenin in brain function and may have important implications for understanding mental retardation syndromes such as Cri-du-Chat and neurodegenerative disorders, such as Alzheimer's disease, that are characterized by cognitive decline.

Analysis of Variance↗
PubMed2004

Memory reconsolidation and extinction have distinct temporal and biochemical signatures.

Memory retrieval is not a passive phenomenon. Instead, it triggers a number of processes that either reinforce or alter stored information. Retrieval is thought to activate a second memory consolidation cascade (reconsolidation) that requires protein synthesis. Here, we show that the temporal dynamics of memory reconsolidation are dependent on the strength and age of the memory, such that younger and weaker memories are more easily reconsolidated than older and stronger memories. We also report that reconsolidation and extinction, two opposing processes triggered by memory retrieval, have distinct biochemical signatures: pharmacological antagonism of either cannabinoid receptor 1 or L-type voltage-gated calcium channels blocks extinction but not reconsolidation. These studies demonstrate the dynamic nature of memory processing after retrieval and represent a first step toward a molecular dissection of underlying mechanisms.

Animals↗
PubMed2004

The involvement of the anterior cingulate cortex in remote contextual fear memory.

Although the molecular, cellular, and systems mechanisms required for initial memory processing have been intensively investigated, those underlying permanent memory storage remain elusive. We present neuroanatomical, pharmacological, and genetic results demonstrating that the anterior cingulate cortex plays a critical role in remote memory for contextual fear conditioning. Imaging of activity-dependent genes shows that the anterior cingulate is activated by remote memory and that this activation is impaired by a null alpha-CaMKII mutation that blocks remote memory. Accordingly, reversible inactivation of this structure in normal mice disrupts remote memory without affecting recent memory.

Animals↗
PubMed2004

Molecular and cellular cognition; the unraveling of memory retrieval.

While the study of molecular and cellular cognition has begun to elucidate the mechanisms of acquisition, consolidation, and storage of memories, the understanding of retrieval has lagged behind. In this issue of Cell, use molecular genetic approaches combined with pharmacology to demonstrate that beta-adrenergic receptor function regulates retrieval of certain forms of memory.

Animals↗
PubMed2004

Consolidation of CS and US representations in associative fear conditioning.

Much attention has been paid to the associative processes that are necessary to fuse together representations of the various components of an episodic memory. In the present study, we focus on the processes involved in the formation of lasting representations of the individual components that make up a fear-conditioning episode. In one-trial contextual fear conditioning experiments, weak conditioning to context occurs if the shock is delivered immediately following placement of the animal in a novel conditioning apparatus, a phenomenon known as the immediate shock deficit. We show that the immediate shock deficit in mice may be alleviated by pre-exposure to either the context or shock. In using this approach to temporally dissect a contextual fear-conditioning task into its constituent representational and associative processes, we are able to examine directly the processes that are important for formation of lasting representations of the context conditioned stimulus (CS) or unconditioned stimulus (US). Our data indicate that the formation of a lasting representation of the context or shock engages protein synthesis-dependent processes. Furthermore, genetic disruption of cAMP-responsive element binding protein (CREB), a transcription factor that regulates the synthesis of new proteins required for long-term memory, disrupts the formation of lasting context memories. We go on to show that the stress hormone epinephrine modulates the consolidation of a context memory, and reverses consolidation deficits in the CREB-deficient mice. Finally we show that disrupting either NMDA or calcium/calmodulin-dependent kinase II (CaMKII) function impairs consolidation of context memories. Together, these data suggest that this approach is particularly suited for the characterization of molecular and cellular processes underlying the formation of stimulus representations.

Animals↗