Bidirectional redistribution of AMPA but not NMDA receptors after perforant path simulation in the adult rat hippocampus in vivo.

Long-term potentiation (LTP) in vitro reveals dynamic regulation of synaptic glutamate receptors. AMPA receptors may be inserted into synapses to increase neurotransmission, whereas NMDA receptors may redistribute within the synapse to alter the probability of subsequent plasticity. To date, the only evidence for these receptor dynamics in the hippocampus is from the studies of dissociated neurons and hippocampal slices taken from young animals. Although synaptic plasticity is induced easily, the extent of AMPA and NMDA receptor mobility after LTP is unknown in the adult, intact hippocampus. To test whether AMPA or NMDAR subunits undergo activity-dependent modifications in adult hippocampal synapses, we induced LTP at perforant path-dentate gyrus (DG) synapses in anesthetized adult rats, using high frequency stimulation (HFS), verified layer-specific Arc induction, and analyzed the distribution of postsynaptic AMPA and NMDAR subunits, using immunogold electron microscopy. The number of synapses with AMPA receptor labeling increased with LTP-inducing HFS in the stimulated region of the dendrite relative to the nonstimulated regions. The opposite trend was noted with low frequency stimulation (LFS). Moreover, HFS increased and LFS decreased the ratio of synaptic to extrasynaptic AMPA receptor labeling in the postsynaptic membrane. In contrast, HFS did not significantly alter NMDAR labeling. Thus, LTP in the adult hippocampus in vivo selectively enhanced AMPA but not NMDAR labeling specifically in synapses undergoing activity-dependent plasticity relative to the remainder of the dendritic tree. The results suggest a mechanism by which rapid adjustments in synaptic strength can occur through localized AMPA receptor mobility and that this process may be competitive across the dendritic tree.

Activity-regulated cytoskeletal-associated protein is localized to recently activated excitatory synapses.

Activity-regulated, cytoskeletal-associated protein (Arc) is an immediate early gene induced in excitatory circuits following behavioral episodes. Arc mRNA is targeted to activated regions of the dendrite after long-term potentiation (LTP) of the dentate gyrus, a process dependent on NMDA receptor activation. We used post-embedding immunogold electron microscopy (EM) to test whether synaptic Arc expression patterns are selectively modified by plasticity. Consistent with previous light microscopic observations, Arc protein was rapidly induced in the dentate gyrus following LTP-producing stimulation of the perforant path and was detectable in granule cell nuclei, somata and dendrites after two hours of high frequency stimulation. Post-embedding EM revealed Arc immunogold labeling in three times as many spines in the middle molecular layer of the stimulated dentate gyrus than in either the ipsilateral outer molecular layer or the contralateral middle and outer molecular layers. This upregulation did not occur with low frequency stimulation of the perforant path. Therefore Arc protein localization may be a powerful tool to isolate recently activated dendritic spines.

Five-year experience with implantation and follow-up of transvenous implantable cardioverter defibrillators: placing postimplant defibrillation threshold testing in perspective.

BACKGROUND: The rapid technological advancement in transvenous implantable cardioverter defibrillators (ICDs) has resulted in heterogeneous and often controversial approaches to follow-up procedures. The efficacy of postimplantation defibrillation threshold (DFT) testing with new-generation biphasic ICDs is unknown. OBJECTIVE: In this retrospective study, predischarge and postdischarge DFT protocols were compared to evaluate their safety and effect on adverse clinical events. METHODS: The study population consisted of 89 patients with 92 ICDs and 103 endovascular lead systems. Forty-four patients had DFT tests during implant and the predischarge period. Thirty patients had DFT tests during implant and the postdischarge period. Sixteen patients had only implant DFT data available. The follow-up period ranged from 3 days to 5.6 years. RESULTS: Ninety-nine percent of patients had successful implants. Postimplant DFT tests detected potential problems in only 1% of asymptomatic patients. Thirty-six percent of patients with normal predischarge DFT tests had adverse clinical events compared with 18% in the postdischarge group. Patients with postimplant DFTs > 25 joules (J) and safety margins > or = 10 J had a lower incidence of adverse clinical events (p = 0.03) compared with those with safety margins < 10 J. An 11% malfunction rate was observed in ICD leads during the follow-up period. CONCLUSIONS: DFT testing after implant is safe; however, routine postimplant DFT testing has limited value in assessing abnormalities in patients with the current generation of biphasic transvenous ICD devices. A 10-J safety margin was associated with a lower incidence of adverse clinical events in patients with DFTs > 25 J. Endovascular lead failure remains a significant problem with ICD systems requiring vigilant follow-up.

Disparate effects of long-term potentiation on evoked potentials and single CA1 neurons in the hippocampus of anesthetized rats.

To examine the effects of long-term potentiation (LTP) on individual neurons in the intact brain, anesthetized rats were implanted with a recording stereotrode in the right CA1 layer of the hippocampus and a stimulating electrode in the right and left CA3 layers. The evoked and spontaneous firing of single CA1 neurons was characterized before and after LTP of the contralateral (commissural) Schaffer collaterals and again after LTP of the ipsilateral (associational) Schaffer collaterals. Individual CA1 neurons displayed either increases or decreases in evoked and spontaneous firing after LTP. As many as five discriminated cells were recorded simultaneously, and they typically responded discordantly, so that after LTP, firing in some neurons increased while in others it decreased. The response of individual neurons to in vivo LTP may be modulated by heterogeneous synaptic changes on individual and local groups of cells, and by changes in feed-forward excitation and inhibition provided by local hippocampal circuitry.

Hippocampus as a memory map: synaptic plasticity and memory encoding by hippocampal neurons.

Hippocampal cells contribute to memory by rapidly encoding information about the perceptual and behavioral structure of experience. This paper describes two complementary experimental approaches that illustrate two important mechanisms that confer these properties to hippocampal cells: (1) Enduring spatial memory and stable place fields each depend upon synaptic plasticity mechanisms that normally rely on the same NMDA-receptor mediated metabolic events as long-term potentiation (LTP). Thus, hippocampal cells "learn" to encode information about the perceptual and behavioral structure of experiences. (2) Hippocampal cells encode the structure of experience and respond in a manner inconsistent with a spatial representation. Place fields are distributed heterogeneously in space, their locations are determined by non-geometric information, the population of active cells can indicate more than one location in space, and hippocampal cells encode discriminative stimuli independent of their spatial location. To the extent that the hippocampus encodes a map, it is more simply described as a memory map than a spatial map. Rather than computing spatial locations, the space it encodes is better described as a life or a problem space that encodes the history of experience into the relational structure of episodes.

Positional firing properties of perirhinal cortex neurons.

Neuronal activity in the perirhinal cortex was recorded while rats performed a spatial task on a four arm radial maze. The maze was defined by proximal multisensory cues on the arm surfaces and distal complex visual cues at the surround. During each recording session, rats were run in three conditions: baseline, a condition in which proximal and distal cues were manipulated, and a second baseline. Compared with the activity of hippocampal neurons in the same paradigm, a much smaller proportion of perirhinal neurons exhibited spatial selectivity and perirhinal place fields were larger than hippocampal place fields. Although perirhinal place fields exhibited a high degree of spatial tuning and reliability within a condition, they were not stable across conditions.

Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein.

Proteolytic processing of amyloid precursor protein (APP) through an endosomal/lysosomal pathway generates carboxy-terminal polypeptides that contain an intact beta-amyloid domain. Cleavage by as-yet unidentified proteases releases the beta-amyloid peptide in soluble form. In Alzheimer's disease, aggregated beta-amyloid is deposited in extracellular neuritic plaques. Although most of the molecular mechanisms involving beta-amyloid and APP in the aetiology of Alzheimer's disease are still unclear, changes in APP metabolism may be important in the pathogenesis of the disease. Here we show that transgenic mice expressing the amyloidogenic carboxy-terminal 104 amino acids of APP develop, with ageing, extracellular beta-amyloid immunoreactivity, increased gliosis and microglial reactivity, as well as cell loss in the CA1 region of the hippocampus. Adult transgenic mice demonstrate spatial-learning deficits in the Morris water maze and in maintenance of long-term potentiation (LTP). Our results indicate that alterations in the processing of APP may have considerable physiological effects on synaptic plasticity.

Hippocampal place fields are altered by the removal of single visual cues in a distance-dependent manner.

Hippocampal CA3 cells were recorded in male Long-Evans rats that explored a square recording chamber. Three of the 4 chamber walls held a rectangular cue card, each of different size. Rotating the set of cue cards rotated the location of the place fields. Place fields were common close to the walls of the recording chamber, particularly the walls with cues. When single cues were removed, the spatial information content decreased but returned to baseline levels when the cue was replaced. When a cue near a place field was removed, the place field firing rate and area decreased; when a distant cue was removed, firing rate and area increased. Thus, removing single visual cues predictably and reversibly altered hippocampal place fields. Together, the results suggest that hippocampal neurons may optimize the encoding of visual information and are consistent with a distance-encoding hypothesis of CA3 network function.

A dose of MK801 previously shown to impair spatial learning in the radial maze attenuates primed burst potentiation in the dentate gyrus of freely moving rats.

Spatial learning but not memory performance in the radial maze is disrupted by low doses of MK801 (0.0625 mg/kg ip), a noncompetitive N-methyl-D-aspartate receptor channel blocker (M. L. Shapiro & C. O'Connor, 1992). The effect of this low dose of MK801 on hippocampal physiology and synaptic plasticity was assessed in 16 behaving female Sprague-Dawley rats. The drug increased the frequency (0.5 Hz), marginally reduced the amplitude of hippocampal rhythmical slow wave activity (RSA), did not alter non-RSA slow wave activity, and reduced normal synaptic transmission from the entorhinal cortex to the dentate gyrus by approximately 8%. Independent of these effects on normal physiology. MK-801 also reduced primed burst potentiation, a form of synaptic plasticity produced by physiologically patterned stimulation, by approximately 20% in the same pathway. Thus, low doses of MK801 may impair spatial learning by reducing, directly or indirectly, the likelihood of synaptic plasticity in the hippocampus.

Discordance of spatial representation in ensembles of hippocampal place cells.

The extent to which small ensembles of neighboring hippocampal neurons alter their spatial firing patterns concurrently in response to stimulus manipulations was examined in young adult rats as well as in aged rats with and without memory impairment. Recordings from CA1 and CA3 cells were taken as rats performed a spatial radial-maze task that employed prominent distal visual stimuli attached to dark curtains surrounding the maze and local cues on each maze arm provided by inserts with distinctive visual, tactile, and olfactory stimuli. To test the influence of the different stimulus subsets, the distal and local cues were rotated 90 degrees in opposite directions (a Double Rotation). In response to this manipulation, place fields could maintain a fixed position to room coordinates, rotate with either the local or the distal cues, disappear, or new fields could appear. On average 79% of the cells within an ensemble responded in the same way, but only 37% of all ensembles were fully concordant. Typically discordant ensembles had place fields that rotated with one set of cues, whereas the other fields disappeared or new fields appeared. Ensembles in which the place fields rotated in two opposite directions were less frequent in young rats than would be expected by the occurrence of the individual responses, indicating selective competition between directly conflicting representations and ultimate suppression of one. These findings indicate that hippocampal neurons independently encode distinct subsets of the cues in a complex environment, although processing within the hippocampal network may actively reduce the simultaneous representation of conflicting orientation information. This kind of population activity might reflect the higher-order organization of new memories within an established knowledge framework or schema. Concordance was higher in aged memory-impaired rats than in young rats, and the suppression of conflicting representations was absent in these rats. These findings suggest that age-related memory impairment is at least in part associated with a decrease in the scope of information coded and in the coordination of encoded representations.

Cues that hippocampal place cells encode: dynamic and hierarchical representation of local and distal stimuli.

Hippocampal place fields were recorded as rats explored a four-arm radial maze surrounded by curtains holding distal stimuli and with distinct local tactile, olfactory, and visual cues covering each arm. Systematic manipulations of the individual cues and their interrelationships showed that different hippocampal neurons encoded individual local and distal cues, relationships among cues within a stimulus set, and the relationship between the local and distal cues. Double rotation trials, which maintained stimulus relationships within distal and local cue sets, but altered the relationship between them, often changed the responses of the sampled neural population and produced new representations. After repeated double rotation trials, the incidence of new representations increased, and the likelihood of a simple rotation with one of the cue sets diminished. Cue scrambling trials, which altered the topological relationship within the local or distal stimulus set, showed that the cells that followed one set of controlled stimuli responded as often to a single cue as to the constellation. These cells followed the single cue when the stimulus constellation was scrambled, but often continued firing in the same place when the stimulus was removed or switched to respond to other cues. When the maze was surrounded by a new stimulus configuration, all of the cells either developed new place fields or stopped firing, showing that the controlled stimuli had persistent and profound influence over hippocampal neurons. Together, the results show that hippocampal neurons encode a hierarchical representation of environmental information.

Ipsilateral associational pathway in the dentate gyrus: an excitatory feedback system that supports N-methyl-D-aspartate-dependent long-term potentiation.

Axons from granule cells in the dentate gyrus of the rat hippocampus project to cells in the hilar region, including mossy cells, which project along the longitudinal axis of the hippocampus and synapse in the inner (proximal) one-third of the molecular layer of the dentate gyrus. To study this feedback system, multiple recording electrodes were located along the longitudinal (septo-temporal) axis in the dorsal leaf of the dentate gyrus in urethane-anesthetized rats. Single pulse electrical stimuli delivered to the hilar region evoked negative-going, monosynaptic field potentials that were largest in the inner one-third of the molecular layer (commissural zone). These evoked field potentials (EFPs) were recorded simultaneously at three to five locations. The latency to onset and peak amplitude of the EFP varied linearly with distance from point of stimulation, and EFPs were elicited in both directions along the longitudinal axis. The transmission speed was estimated to be 1.4 m/s. Tetanic stimulation of the hilar region potentiated the EFP slopes (mean = 26%). Potentiation lasted at least 2 hours and was specific to responses from the tetanized stimulating electrode; the responses to other stimulating electrodes in the hilus and the angular bundle of the perforant path changed less than 4%. Combined stimulation of the hilus and the medial perforant path increased the magnitude of recorded field potentials and population spikes, demonstrating that both pathways are excitatory. NMDA antagonist NPC-17742 blocked potentiation of EFP slopes in both the medial perforant path and hilus pathways. The results suggest that the ipsilateral associational system of the dentate gyrus is excitatory and capable of supporting long-lasting NMDA-dependent, synapse-specific plasticity.

Spatial memory and N-methyl-D-aspartate receptor antagonists APV and MK-801: memory impairments depend on familiarity with the environment, drug dose, and training duration.

Rats given N-methyl-D-aspartate (NMDA) antagonists were tested in the radial maze in spatial working memory (WM) and reference memory (RM) tasks. Female rats given (+)-10,11-dihydro-5-methyl-5H-dibenzo [a,d] cycloheptene-5,10 imine (MK-801; 0.0625 mg/kg ip) before daily testing in an 8-arm WM task were impaired even after 70 days. Control rats learned quickly, were assigned to a group given MK-801 or saline, and were trained to avoid 4 of the 8 arms. MK-801 impaired this reversal learning but did not affect WM performance. Male rats were trained on an 8-arm WM task for 19 days and then given intracranial aminophosphonovaleric acid (APV; 33 mM), which impaired both WM and motor behavior. Male rats were trained for 65 days to enter 4 of 8 arms and then given intracranial APV (20 or 30 mM). WM and RM were normal in the familiar environment but were both impaired in an unfamiliar environment. Results suggest that the mnemonic effects of NMDA antagonists depend on environmental familiarity, dose, and training duration.

A simple network model simulates hippocampal place fields: II. Computing goal-directed trajectories and memory fields.

Place cells have been described as the computational elements of a neuronal cognitive mapping system that encodes and stores relationships among spatial stimuli (O'Keefe & Nadel, 1978). Furthermore, place cells seem to encode remembered locations because neural activity is maintained when the visual stimuli that influence place field location are vastly degraded, such as when cues are removed or the lights are turned off (O'Keefe & Speakman, 1987; Quirk, Muller, & Kubie, 1990). A feed-forward network model that mapped visual input onto a representation of location simulated some basic properties of hippocampal place fields, including resistance to disruption after partial cue removal (Shapiro & Hetherington, 1993). However, the stimulated place fields required visual input for their activation. We now report that a network that incorporates feedback (a) computed correct trajectories toward simulated goals and (b) simulated place fields that persist in the absence of visual input. The simulation suggests that feedback properties can provide a computational account of O'Keefe and Speakman's data.

Normal ovaries in neonates and infants: a sonographic study of 77 patients 1 day to 24 months old.

OBJECTIVE: Normal values for ovarian measurements in adults have been revised over the past decade. A recent report stated that ovarian cysts were common in healthy girls 2-13 years old, refuting the findings of a 1984 study. No large sonographic study of normal ovaries in girls 1 day to 24 months old has been performed. We evaluated ovaries in girls in this age group to determine the normal volume and prevalence of ovarian cysts. SUBJECTS AND METHODS: The ovaries of 77 consecutive patients 1 day to 24 months old were evaluated during routine pelvic sonography. Patients were divided into three age groups: 1 day to 3 months old (when gonadotropin levels are highest because of loss of placental hormonal influence), 4-12 months old (an intermediate group), and 13-24 months old (when gonadotropin levels are low). RESULTS: Ninety-eight ovaries were imaged in three dimensions. The mean volume was 1.06 cm3 (range, 0.7-3.6 cm3) among girls up to 3 months old; 1.05 cm3 (range, 0.2-2.7 cm3) among girls 4-12 months old; and 0.67 cm3 (range, 0.1-1.7 cm3) among girls 13-24 months old. We found no significant difference in mean volumes among the three groups. The prevalence of ovarian cysts was similar in all three groups; ovarian cysts were seen in 84% of all imaged ovaries. Macrocysts (cysts larger than 9 mm) were seen in 18% of all cystic ovaries. CONCLUSION: Ovaries of girls 1 day to 24 months old can have volumes greater than 1 cm3. Ovarian cysts are common. Macrocysts can be seen despite claims that they are rare in girls less than 11 years old.

A simple network model simulates hippocampal place fields: parametric analyses and physiological predictions.

Hippocampal place cells may be the computational units of a neuronal cognitive mapping system. A network model trained to compute locations from distal cues simulated the defining properties of hippocampal place cells (i.e., place-specific activation). The model produced units with detailed properties of place cells, including multiple subfields, "silent" and "noisy" cells, fields that persisted after cue removal, and groups of simulated fields that overlapped in multiple clusters. Quantitative variants of the model showed that different properties of the fields were influenced by the complexity of the visual input (the number of spatial cues), the available computational resources (the number of hidden units), and the output encoding used to represent location. The simulations provide a framework for testing relationships between place field properties, variations in spatial environments, and the integrity of the hippocampal system.

N-methyl-D-aspartate receptor antagonist MK-801 and spatial memory representation: working memory is impaired in an unfamiliar environment but not in a familiar environment.

Female Sprague-Dawley rats were injected with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 or saline 30 min before daily testing in spatial working memory (WM) and reference memory (RM) procedures in an 8-arm radial maze. MK-801 impaired RM and WM acquisition but not performance when rats were trained to criterion before drug administration. Neither a 2-hr nor a 4-hr delay between the first and last 2 correct WM choices impaired long-term WM. MK-801 impaired WM performance in trained rats only when rats were tested in a new environment. Thus, 2 mechanisms may be required for relational memory: an NMDA-dependent mechanism for acquiring long-term spatial representations and an NMDA-insensitive mechanism for operating on these stored representations.