Biomedical subjects

Christopher S Rex

Publications and source records attributed to Christopher S Rex.

6 recordsLinked to original sources

PubMed2006

LTP consolidation: substrates, explanatory power, and functional significance.

Long-term potentiation (LTP) resembles memory in that it is initially unstable and then, over about 30 min, becomes increasingly resistant to disruption. Here we present an hypothesis to account for this initial consolidation effect and consider implications that follow from it. Anatomical studies indicate that LTP is accompanied by changes in spine morphology and therefore likely involves cytoskeletal changes. Accordingly, theta bursts initiate calpain-mediated proteolysis of the actin cross-linking protein spectrin and trigger actin polymerization in spine heads, two effects indicative of cytoskeletal reorganization. Polymerization occurs within 2 min, has the same threshold as LTP, is dependent on integrins, and becomes resistant to disruption over 30 min. We propose that the stabilization of the new cytoskeletal organization, and thus of a new spine morphology, underlies the initial phase of LTP consolidation. This hypothesis helps explain the diverse array of proteins and signaling cascades implicated in LTP, as well as the often-contradictory results about contributions of particular molecules. It also provides a novel explanation for why LTP is potently modulated by factors likely to be released during theta trains (e.g., BDNF). Finally, building on evidence that normal patterns of activity reverse LTP, we suggest that consolidation provides a delay that allows brain networks to sculpt newly formed memories.

Animals↗

PubMed2006

Synaptic plasticity in early aging.

Studies of how aging affects brain plasticity have largely focused on old animals. However, deterioration of memory begins well in advance of old age in animals, including humans; the present review is concerned with the possibility that changes in synaptic plasticity, as found in the long-term potentiation (LTP) effect, are responsible for this. Recent results indicate that impairments to LTP are in fact present by early middle age in rats but only in certain dendritic domains. The search for the origins of these early aging effects necessarily involves ongoing analyses of how LTP is induced, expressed, and stabilized. Such work points to the conclusion that cellular mechanisms responsible for LTP are redundant and modulated both positively and negatively by factors released during induction of potentiation. Tests for causes of the localized failure of LTP during early aging suggest that the problem lies in excessive activity of a negative modulator. The view of LTP as having redundant and modulated substrates also suggests a number of approaches for reversing age-related losses. Particular attention will be given to the idea that induction of brain-derived neurotrophic factor, an extremely potent positive modulator, can be used to provide long periods of normal plasticity with very brief pharmacological interventions. The review concludes with a consideration of how the selective, regional deficits in LTP found in early middle age might be related to the global phenomenon of brain aging.

Aging↗

PubMed2006

Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor.

Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP.

Aging↗

PubMed2006

Integrin-driven actin polymerization consolidates long-term potentiation.

Long-term potentiation (LTP), like memory, becomes progressively more resistant to disruption with time after its formation. Here we show that threshold conditions for inducing LTP cause a rapid, long-lasting increase in polymerized filamentous actin in dendritic spines of adult hippocampus. Two independent manipulations that reverse LTP disrupted this effect when applied shortly after induction but not 30 min later. Function-blocking antibodies to beta1 family integrins selectively eliminated both actin polymerization and stabilization of LTP. We propose that the initial stages of consolidation involve integrin-driven events common to cells engaged in activities that require rapid morphological changes.

Actins↗

PubMed2005

Long-term potentiation is impaired in middle-aged rats: regional specificity and reversal by adenosine receptor antagonists.

Memory loss in humans begins early in adult life and progresses thereafter. It is not known whether these losses reflect the failure of cellular processes that encode memory or disturbances in events that retrieve it. Here, we report that impairments in hippocampal long-term potentiation (LTP), a form of synaptic plasticity associated with memory, are present by middle age in rats but only in select portions of pyramidal cell dendritic trees. Specifically, LTP induced with theta-burst stimulation in basal dendrites of hippocampal field CA1 decayed rapidly in slices prepared from 7- to 10-month-old rats but not in slices from young adults. There were no evident age-related differences in LTP in the apical dendrites. Both the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and a positive AMPA receptor modulator (ampakine) offset age-related LTP deficits. Adenosine produced greater depression of synaptic responses in middle-aged versus young adult slices and in basal versus apical dendrites. These results were not associated with variations in A1 receptor densities and may instead reflect regional and age-related differences in adenosine clearance. Pertinent to this, brief applications of A1 receptor antagonists immediately after theta stimulation fully restored LTP in middle-aged rats. We hypothesize that the build-up of extracellular adenosine during theta activity persists into the postinduction period in the basal dendrites of middle-aged slices and thereby activates the A1 receptor-dependent LTP reversal effect. Regardless of the underlying mechanism, the present results provide a candidate explanation for memory losses during normal aging and indicate that, with regard to plasticity, different segments of pyramidal neurons age at different rates.

Aging↗

PubMed2004

Long-term potentiation is impaired in rat hippocampal slices that produce spontaneous sharp waves.

Sharp waves (SPWs) occur in the hippocampal EEG during behaviours such as alert immobility and slow-wave sleep. Despite their widespread occurrence across brain regions and mammalian species, the functional importance of SPWs remains unknown. Experiments in the present study indicate that long-term potentiation (LTP) is significantly impaired in slices, prepared from the temporal aspect of rat hippocampus, that spontaneously generate SPW activity. This was probably not due to anatomical and/or biochemical abnormalities in temporal slices because stable LTP was uncovered in field CA1 when SPWs were eliminated by severing the projection from CA3. The same procedure did not alter LTP in slices lacking SPWs. Robust and stable LTP was obtained in the presence of SPWs in slices treated with an adenosine A1 receptor antagonist, a finding that links the present results to mechanisms related to the LTP reversal effect. In accord with this, single stimulation pulses delivered intermittently in a manner similar to the SPW pattern interfered with LTP to a similar degree as spontaneous SPWs. Taken together, these results suggest the possibility that SPWs in the hippocampus constitute a neural mechanism for forgetting.

6-Cyano-7-nitroquinoxaline-2,3-dione↗