Calcium-Dependent But Action Potential-Independent BCM-Like Metaplasticity in the Hippocampus

The Bienenstock, Cooper and Munro (BCM) computational model, which incorporates a metaplastic sliding threshold for LTP induction, accounts well for experience-dependent changes in synaptic plasticity in the visual cortex. BCM-like metaplasticity over a shorter timescale has also been observed in the hippocampus, thus providing a tractable experimental preparation for testing specific predictions of the model. Here, using extracellular and intracellular electrophysiological recordings from acute rat hippocampal slices, we tested the critical BCM predictions (1) that high levels of synaptic activation will induce a metaplastic state that spreads across dendritic compartments, and (2) that postsynaptic cell-firing is the critical trigger for inducing that state. In support of the first premise, high-frequency priming stimulation inhibited subsequent long-term potentiation and facilitated subsequent long-term depression at synapses quiescent during priming, including those located in a dendritic compartment different to that of the primed pathway. These effects were not dependent on changes in synaptic inhibition or NMDA/ metabotropic glutamate receptor function. However, in contrast to the BCM prediction, somatic action potentials during priming were neither necessary nor sufficient to induce the metaplasticity effect. Instead, in broad agreement with derivatives of the BCM model, calcium as released from intracellular stores and triggered byM1 muscarinic acetylcholine receptor activation was critical for altering subsequent synapticplasticity. These results indicate that synaptic plasticity in stratum radiatum of CA1 can be homeostatically regulated by the cell-wide history of synaptic activity through a calcium-dependent but action potential-independent mechanis

Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms

Lentiviruses have been extensively used as gene delivery vectors since the mid-1990s. Usually derived from the human immunodeficiency virus genome, they mediate efficient gene transfer to non-dividing cells, including neurons and glia in the adult mammalian brain. In addition, integration of the recombinant lentiviral construct into the host genome provides permanent expression, including the progeny of dividing neural precursors. In this review, we describe targeted vectors with modified envelope glycoproteins and expression of transgenes under the regulation of cell-selective and inducible promoters. This technology has broad utility to address fundamental questions in neuroscience and we outline how this has been used in rodents and primates. Combining viral tract tracing with immunohistochemistry and confocal or electron microscopy, lentiviral vectors provide a tool to selectively label and trace specific neuronal populations at gross or ultrastructural levels. Additionally, new generation optogenetic technologies can be readily utilized to analyze neuronal circuit and gene functions in the mature mammalian brain. Examples of these applications, limitations of current systems and prospects for future developments to enhance neuroscience knowledge will be reviewed. Finally, we will discuss how these vectors may be translated from gene therapy trials into the clinical setting

The Economic Effects and Problems of Housing Reconstruction Policy : Evaluating Public Housing

Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses

Physiological effects of enriched environment exposure and LTP induction in the hippocampus in vivo do not transfer faithfully to in vitro slices

A number of experimental paradigms use in vitro brain slices to test for changes in synaptic transmission and plasticity following a behavioral manipulation. For example, a number of previous studies have reported a variety of effects of environmental enrichment (EE) exposure on field potential responses in hippocampal slices, but in no study was is it known what changes had been elicited in vivo. In the present study, we recorded from the hippocampus in vivo while rats underwent a brief period of EE. There was no detectable EE-induced change in synaptic efficacy in the dentate gyrus in vivo, but there was an increase in cellular excitability. In slices prepared from the same animals, we failed to observe any evidence of the excitability increase. We next tested whether LTP induction in vivo was better preserved in vitro. However, when slices from these rats were examined, there was no observable change in perforant path synaptic strength, although there was a modest increase in excitability that correlated with the increased excitability observed in vivo. These findings suggest that synaptic changes induced in vivo either are not preserved faithfully or are difficult to detect in hippocampal slices, while changes in cellular excitability are better preserved

Glutamate receptors and metaplasticity in addiction

Chronic drug use is a neuroadaptive disorder characterized by strong and persistent plasticity in the mesocorticolimbic reward system. Long-lasting effects of drugs of abuse rely on their ability to hijack glutamate receptor activity and long-term synaptic plasticity processes like long-term potentiation and depression. Importantly, metaplasticity-based modulation of synaptic plasticity contributes to durable neurotransmission changes in mesocorticolimbic pathways including the ventral tegmental area and the nucleus accumbens, causing 'maladaptive' drug memory and higher risk for drug-seeking relapse. On the other hand, drug-induced metaplasticity can make appetitive memories more malleable to modification, offering a potential target mechanism for intervention. Here we review the literature on the role of glutamate receptors in addiction-related metaplasticity phenomena