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PubMed2001

Effect of lamotrigine treatment on status epilepticus-induced neuronal damage and memory impairment in rat.

Status epilepticus causes neuronal damage that is associated with cognitive impairment. The present study examined whether a novel antiepileptic drug, lamotrigine (LTG), alleviates status epilepticus-induced temporal lobe damage and memory impairment, and compared its efficacy with carbamazepine. Status epilepticus was induced by electric stimulation of the perforant pathway (PP) in rats. Treatment with LTG (12.5 mg/kg, twice a day) was started either 3 days before (preLTG group) or 1 h after (postLTG group) a 60 min PP stimulation. Treatment with carbamazepine (CBZ; 30 mg/kg, twice a day) was started 3 days before (CBZ group) a 60 min PP stimulation. All treatments were continued for 2 weeks. Thereafter, the severity of seizures, seizure-induced neuronal damage, quantitative electroencephalogram (EEG), and memory impairment were compared between vehicle-treated unstimulated and stimulated controls, LTG-treated rats, and CBZ-pretreated rats. Both in the preLTG and postLTG groups, damage to hilar somatostatin-immunoreactive neurons, hippocampal CA3b and CA3a pyramidal cells, and the piriform cortex was mild and did not differ from that in unstimulated controls. Furthermore, CA3c damage in the preLTG group did not differ from that in unstimulated controls. Vehicle-treated stimulated controls and CBZ-pretreated rats, however, had significant damage in the hilus, CA3 subregions, and piriform cortex compared with unstimulated controls (P<0.05 for the stimulated side, contralateral side, or both). Treatment with LTG or CBZ had no effect on the number or duration of behavioral seizures during PP stimulation. They did not affect the baseline EEG or status epilepticus-induced slowing of the EEG. Also, the status epilepticus-induced spatial memory impairment in the Morris water-maze was not attenuated by treatment with LTG or CBZ. Our data demonstrate that treatment with LTG has a mild neuroprotective effect on status epilepticus-induced neuronal damage in rats even when administered after the beginning of status epilepticus.

Animals↗
PubMed1996

PC-2, linear homoglucan with alpha-linkages, peripherally enhances the hippocampal long-term potentiation.

PURPOSE: To investigate central effectiveness of PC-2, a glucan from lichen Parmelia caperata with alpha(1-3)(1-4) linkages in the ratio 3:2, with regard to the long-term potentiation (LTP) of evoked potential. METHODS: The extent of LTP, induced by high-frequency stimulation of medial perforant pathway, was evaluated as fractional increase in population spike amplitude in dentate gyrus in anesthetized rats. RESULTS: Oral and intravenous application of PC-2 resulted in significant enhancement of LTP elicited by a weak, but not by a strong, tetanic stimulation. No influence of PC-2 on basal evoked synaptic potential was found. Bilateral adrenalectomy profoundly suppressed the positive impact of the glucan on the formation of LTP, but showed no effect upon the magnitude and time-course of population spike enhancement in vehicle-treated subjects. Two related alpha-glucans with different chemical structures did not show any effect comparable to that of PC-2. CONCLUSIONS: Peripheral application of PC-2 significantly enhances LTP in dentate gyrus in rats. Results indicate that the effect of PC-2 might be peripherally mediated and that the specific higher structure of PC-2 is crucial for its biological activity.

Adrenalectomy↗
PubMed1987

Effects of aging on environmental modulation of hippocampal evoked responses.

Evoked responses in the dentate gyrus of the hippocampal formation undergo a long-term enhancement following high-frequency stimulation of the perforant pathway. A similar change results from exposure of animals to a complex spatial environment. The effect of aging on the development and decay of this environmentally induced response enhancement was examined in the present study. Previously it was shown that electrically induced enhancement reaches the same asymptotic level in young and old animals but decays more quickly in old animals. It has been suggested that this faster decay may underlie the faster forgetting of spatial information observed in old animals. Chronic recordings were made from young (14 month) and old (32 month) rats. After exposure to an enriched environment for 11 days, the population spike component of the response increased about 125% over baseline in both groups. No changes were seen in either group in the synaptic component. Following the enrichment treatment, animals were returned to their home cages. The decay of the enhanced population spike during this period differed markedly between age-groups (time constants of 30 and 11 days for the young and old groups, respectively). These results suggest that the factors governing the decay of electrically and environmentally induced response enhancement are similarly affected by the aging process and may share a common mechanism.

Afferent Pathways↗
PubMed2005

Impaired fear memories are correlated with subregion-specific deficits in hippocampal and amygdalar LTP.

Inbred mouse strains have different genetic backgrounds that likely influence memory and long-term potentiation (LTP). LTP, a form of synaptic plasticity, is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired fear memory may have selective LTP deficits in different hippocampal subregions or in the amygdala. The authors assessed fear memory in 4 inbred strains: C57BL/6NCrlBR (B6), 129S1/SvImJ (129), C3H/HeJ (C3H), and DBA/2J (D2). The authors also measured LTP in the hippocampal Schaeffer collateral (SC) and medial perforant pathways (MPP) and in the basolateral amygdala. Contextual and cued fear memory, and SC and amygdalar LTP, were intact in B6 and 129, but all were impaired in C3H and D2. MPP LTP was similar in all 4 strains. Thus, SC, but not MPP, LTP correlates with hippocampus-dependent contextual memory expression, and amygdalar LTP correlates with amygdala-dependent cued memory expression, in these inbred strains.

Amygdala↗
PubMed1988

Calcium uptake evoked by electrical stimulation is enhanced postischemically and precedes delayed neuronal death in CA1 of rat hippocampus: involvement of N-methyl-D-aspartate receptors.

Extracellular calcium concentration changes in the CA1 of the hippocampus during burst activity were measured during postischemic reflow, and the involvement of N-methyl-D-aspartate (NMDA) receptors was evaluated. In adult Wistar rats global ischemia was induced by four-vessel occlusion for 20 min. After 6 h of postischemic reflow, the animals were halothane-anesthetized and reintubated. A double-barrelled calcium-sensitive microelectrode was advanced through stratum oriens, pyramidale, and radiatum in 50-micron steps. At each step the perforant pathway was stimulated (15 Hz, 30 s), and changes in extracellular calcium concentration were recorded. High-frequency stimulation elicited burst firing and transient decreases in extracellular calcium concentration, which are interpreted as neuronal calcium uptake. In control hippocampus, the extracellular calcium decreases were maximal in the stratum pyramidale. Six to eight hours after ischemia, a threefold enhancement of extracellular calcium decreases was found in the dendritic layers of the CA1. The NMDA-receptor antagonist ketamine (15-30 mg/kg intraperitoneally) reduced these electrically evoked calcium decreases. Seven days after ischemia, there was a 60-90% loss of pyramidal cells in the CA1. In conclusion, the cellular calcium uptake, possibly through NMDA receptors evoked by neuronal activity, is enhanced during early postischemia and precedes delayed neuronal death.

Animals↗
PubMed1992

Enhanced calcium uptake by CA1 pyramidal cell dendrites in the postischemic phase despite subnormal evoked field potentials: excitatory amino acid receptor dependency and relationship to neuronal damage.

After 6-12 h of recovery from transient cerebral ischemia, the pyramidal cells of the hippocampal CA1 region take up excessive amounts of calcium upon electrical stimulation, which has been suggested to be important for the development of delayed neuronal death. The aim of this study was to further characterize this enhanced calcium uptake with respect to time-course of development, relationship to neuronal damage, and amplitude of evoked field potentials as well as the dependency on N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Adult Wistar rats were used and calcium-sensitive microelectrodes were placed in the stratum radiatum of the CA1 hippocampus for recording of the extracellular calcium concentration ([Ca2+]ec) during 20 min of ischemia and for 6 h of reflow. High-frequency stimulation of the perforant pathway elicited burst firing in CA1 and a transient decrease in [Ca2+]ec which reflects neuronal uptake. Shifts in [Ca2+]ec could not be evoked 0-1 h after ischemia. However, from 1-2 h burst firing could be evoked and the accompanying shift in [Ca2+]ec increased thereafter in amplitude with prolonged reflow, exceeded preischemic levels after 4 h, and reached 250 +/- 116% (mean +/- SD) of control after 6 h of reflow (p less than 0.05). The extracellular reference potential shift during electrical stimulation and the amplitude of evoked field potentials were still subnormal after 6 h [85 +/- 25% and 83 +/- 25%, respectively (mean +/- SD)]. There was a significant correlation between the degree of stimulated calcium uptake at 6 h postischemia and the extent of CA1 damage evaluated 7 days after the ischemic insult (r = 0.849; p less than 0.001). The shifts in [Ca2+]ec were reduced by the NMDA antagonist MK-801 (0.5-2 mg/kg, i.v.) to approximately 50% of the initial level during both control and postischemic conditions (p less than 0.01). The non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[F]quinoxaline (NBQX) (42 +/- 13 mg/kg, i.p.; mean +/- SD) decreased the amplitude of the evoked field potentials (to 30 +/- 28% of control, p less than 0.05) and completely abolished the evoked shifts in [Ca2+]ec. In conclusion, the uptake of calcium into CA1 pyramidal cells during electrical stimulation was enhanced already 4 h after ischemia in spite of the fact that other measures of excitability were subnormal. This calcium uptake correlated to the extent of CA1 pyramidal cell damage and was dependent on both NMDA and non-NMDA receptor activation.

Analysis of Variance↗
PubMed2000

Repeated long-term potentiation induces mossy fibre sprouting and changes the sensibility of hippocampal granule cells to subconvulsive doses of pentylenetetrazol.

Electrical and chemical kindling induces sprouting of the mossy fibre system and potentiation of evoked field potentials in the dentate gyrus. It has been postulated that such changes may also be induced by repeated induction of long-term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP was induced in rats chronically implanted with stimulation electrodes in the ipsilateral and contralateral angular bundles and with a recording electrode in the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10 consecutive days but with different tetanization strengths. Sprouting of the mossy fibres terminating in the CA3 region was significantly induced only in the group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized animals, or in low-frequency stimulated animals. Additionally, a novel form of potentiation which was previously found in pentylenetetrazol (PTZ)-kindled animals was also observed in the group of 'strongly' and 'weakly' tetanized rats. Differences in duration of this potentiation were found between the two groups of animals tetanized with different strengths. The results further demonstrate that morphological and functional changes in the hippocampus, similar to those seen after kindling, can also occur in an activation paradigm leading to long-lasting synaptic plasticity but not accompanied by seizure activity.

Action Potentials↗
PubMed1997

Rapid changes in local extracellular rat brain glucose observed with an in vivo glucose sensor.

A needle-type electrochemically based microsensor for glucose (110 microns o.d.) is described. This sensor, designed for monitoring transient glucose content changes in response to neural stimuli, has a response time of approximately 5 s and has been shown to be free of interference from endogenous electroactive species such as ascorbate, urate, and various neurotransmitters. It exhibits linear response to glucose up to 10 mM. The usefulness of the sensor has been demonstrated by examining the time-dependent interstitial glucose concentration in the rat hippocampus in response to KCl depolarization and by stimulation of glutamate neurons through a perforant pathway. Simultaneous monitoring of oxygen is also carried out and demonstrates that for both oxygen and glucose there is substantial local depletion of both species and that their pools are replenished by increased regional cerebral blood flow. The transient initial rapid (10-13 s) decrease up to 20-34%, observed on a time scale comparable to that for neurotransmitter release, may be involved in a recently suggested astrocytic uptake for glutamate-stimulated aerobic glycolysis possibly needed to meet energy homeostasis in brain. These studies demonstrate the importance of microsensors in monitoring transient events linked to neuronal stimulation.

Animals↗
PubMed1997

A temporary local energy pool coupled to neuronal activity: fluctuations of extracellular lactate levels in rat brain monitored with rapid-response enzyme-based sensor.

A successfully developed enzyme-based lactate microsensor with rapid response time allows the direct and continuous in vivo measurement of lactic acid concentration with high temporal resolution in brain extracellular fluid. The fluctuations coupled to neuronal activity in extracellular lactate concentration were explored in the dentate gyrus of the hippocampus of the rat brain after electrical stimulation of the perforant pathway. Extracellular glucose and oxygen levels were also detected simultaneously by coimplantation of a fast-response glucose sensor and an oxygen electrode, to provide novel information of trafficking of energy substances in real time related to local neuronal activity. The results first give a comprehensive picture of complementary energy supply and use of lactate and glucose in the intact brain tissue. In response to acute neuronal activation, the brain tissue shifts immediately to significant energy supply by lactate. A local temporary fuel "reservoir" is established behind the blood-brain barrier, evidenced by increased extracellular lactate concentration. The pool can be depleted rapidly, up to 28% in 10-12 s, by massive, acute neuronal use after stimulation and can be replenished in approximately 20 s. Glutamate-stimulated astrocytic glycolysis and the increase of regional blood flow may regulate the lactate concentration of the pool in different time scales to maintain local energy homeostasis.

Animals↗
PubMed1991

Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy.

Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death, which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney, J. W. (1978) in Kainic Acid as a Tool in Neurobiology, eds. McGeer, E., Olney, J. W. & McGeer, P. (Raven, New York), pp. 95-121; Olney, J. W. (1983) in Excitotoxins, eds. Fuxe, K., Roberts, P. J. & Schwartch, R. (Wenner-Gren International Symposium Series, Macmillan, London), Vol. 39, pp. 82-96; and Rothman, S. M. & Olney, J. W. (1986) Ann. Neurol. 19, 105-111] predicts an imbalance between excitation and inhibition, which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study, we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme, GABA transaminase, could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA, and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and, as a result, protect the brain from seizure-induced cognitive impairment.

4-Aminobutyrate Transaminase↗
PubMed2001

Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase.

Central infusion of angiotensin IV or its more stable analogues facilitates memory retention and retrieval in normal animals and reverses amnesia induced by scopolamine or by bilateral perforant pathway lesions. These peptides bind with high affinity and specificity to a novel binding site designated the angiotensin AT(4) receptor. Until now, the AT(4) receptor has eluded molecular characterization. Here we identify the AT(4) receptor, by protein purification and peptide sequencing, to be insulin-regulated aminopeptidase (IRAP). HEK 293T cells transfected with IRAP exhibit typical AT(4) receptor binding characteristics; the AT(4) receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [(125)I]Nle(1)-angiotensin IV with IC(50) values of 32 and 140 nm, respectively. The distribution of IRAP and its mRNA in the brain, determined by immunohistochemistry and hybridization histochemistry, parallels that of the AT(4) receptor determined by radioligand binding. We also show that AT(4) receptor ligands dose-dependently inhibit the catalytic activity of IRAP. We have therefore demonstrated that the AT(4) receptor is IRAP and propose that AT(4) receptor ligands may exert their effects by inhibiting the catalytic activity of IRAP thereby extending the half-life of its neuropeptide substrates.

Aminopeptidases↗
PubMed2005

Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury.

The present study examined the neuropathology of the lateral controlled cortical impact (CCI) traumatic brain injury (TBI) model in mice utilizing the de Olmos silver staining method that selectively identifies degenerating neurons and their processes. The time course of ipsilateral and contralateral neurodegeneration was assessed at 6, 24, 48, 72, and 168 h after a severe (1.0 mm, 3.5 M/sec) injury in young adult CF-1 mice. At 6 hrs, neurodegeneration was apparent in all layers of the ipsilateral cortex at the epicenter of the injury. A low level of degeneration was also detected within the outer molecular layer of the underlying hippocampal dentate gyrus and to the mossy fiber projections in the CA3 pyramidal subregions. A time-dependent increase in cortical and hippocampal neurodegeneration was observed between 6 and 72 hrs post-injury. At 24 h, neurodegeneration was apparent in the CA1 and CA3 pyramidal and dentate gyral granule neurons and in the dorsolateral portions of the thalamus. Image analysis disclosed that the overall volume of ipsilateral silver staining was maximal at 48 h. In the case of the hippocampus, staining was generalized at 48 and 72 h, indicative of damage to all of the major afferent pathways: perforant path, mossy fibers and Schaffer collaterals as well as the efferent CA1 pyramidal axons. The hippocampal neurodegeneration was preceded by a significant increase in the levels of calpain-mediated breakdown products of the cytoskeletal protein alpha-spectrin that began at 6 h, and persisted out to 72 h post-injury. Damage to the corpus callosal fibers was observed as early as 24 h. An anterior to posterior examination of neurodegeneration showed that the cortical damage included the visual cortex. At 168 h (7 days), neurodegeneration in the ipsilateral cortex and hippocampus had largely abated except for ongoing staining in the cortical areas surrounding the contusion lesion and in hippocampal mossy fiber projections. Callosal and thalamic neurodegeneration was also very intense. This more complete neuropathological examination of the CCI model shows that the associated damage is much more widespread than previously appreciated. The extent of ipsilateral and contralateral neurodegeneration provides a more complete anatomical correlate for the cognitive and motor dysfunction seen in this paradigm and suggests that visual disturbances are also likely to be involved in the post-CCI neurological deficits.

Animals↗
PubMed1993

NMDA-sensitive [3H]glutamate binding in the epileptic rat hippocampus: an autoradiographic study.

Sustained stimulation of the perforant pathway (PP) offers a model for studying seizure-induced pathology of the hippocampal formation. Using quantitative autoradiography, NMDA-sensitive glutamate binding was evaluated in the rat hippocampus three weeks after PP-stimulation. Decreased receptor binding (38-44%) was found together with pyramidal cell damage and gliosis in the CA1 area, ipsilateral to the stimulation (p < or = 0.001). In the dentate gyrus, however, a 20% increase in receptor density was observed bilaterally within the molecular layer (significant within the outer molecular layer of the contralateral side, on the suprapyramidal location; p < or = 0.05). These results are similar to those found in epileptic patients and suggest a prominent role for NMDA receptors in epilepsy.

Animals↗
PubMed1994

Type I adrenal steroid receptors prolong hippocampal long-term potentiation.

The effects of Type I adrenal steroid receptors in prolonging synaptic plasticity in the dentate gyrus of freely behaving rats was investigated. Rats were implanted with chronic, bilateral stimulating and recording electrodes in the perforant pathway and dentate gyrus, respectively, and adrenalectomized (ADX). After a 2-3 day recovery period, baseline recordings of field potentials were made followed by administration of aldosterone or vehicle. One hour later, high frequency stimulation (HFS; chosen to produce comparable long-term potentiation (LTP) in the aldosterone-treated and control groups) was applied unilaterally and recording was continued for 1 h and again performed at 3, 24 and 48 h. LTP in ADX controls decayed significantly within 3 h, and returned to baseline levels at 24 h. In contrast, the aldosterone-treated animals showed enhanced LTP at 3, 24 and 48 h. These findings demonstrate that aldosterone both enhances and prolongs hippocampal plasticity.

Adrenal Glands↗
PubMed1997

Dopaminergic modulation of LTP induction in the dentate gyrus of intact brain.

The effect of the dopamine system on the induction of long-term potentiation (LTP) in the dentate gyrus was studied in anesthetized rats. A subthreshold tetanic train (seven pulses at 100 Hz) given to the perforant pathway, which usually fails to elicit LTP, potentiated a slope of field excitatory postsynaptic potentiation (fEPSP) measured from the hilus of the dentate gyrus when a precursor for catecholamine, L-3,4-dihydroxyphenylalanine (L-DOPA), was administered orally to rats. The increase in the fEPSP slope persisted for at least 60 min. Intraventricular injection of a specific dopamine D1/D5 agonist, SKF38393, mimicked the effect of L-DOPA, suggesting an involvement of D1/D5 receptors in the induction of dentate gyrus LTP. Consistent with this, intraventricular administration of the D1/D5 antagonist SCH23390 resulted in complete inhibition of LTP induction by a longer tetanus (100 pulses at 100 Hz), which usually elicits a robust LTP. Thus, D1/D5 receptor activation appears to modulate LTP induction in vivo.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Potentiation of phosphoinositide-derived signals during LTP in intact rat brain.

In order to examine the relationship between long-term potentiation (LTP) and phosphoinositide (PI) turnover, we evaluated these throughout anesthetized rat brain using carbon-11-labeled diacylglycerol (11C-DAG). High-frequency tetanic stimulation (400 pulses at 400 Hz) to the perforant pathway induced LTP in rat dentate gyrus. In autoradiograms of rat brains, LTP was associated with the occurrence of multiple highly radioactive spots in many regions distant from the stimulated site. Following i.v. administration of an NMDA receptor antagonist prior to stimulation, however, no high-density spots were found. These findings directly demonstrate that potentiation of phosphoinositide-derived signaling was induced during LTP, and the finding of multiple location suggests the occurrence of polysynaptic neurotransmission through neural networks pertaining to learning and memory.

Animals↗
PubMed1997

Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus.

Microglial cells are the main component of the brain's resident immune system and are activated in Alzheimer disease (AD). We quantified the density of activated microglial cells (AMG) in 8 sectors of human hippocampus to determine if their density is correlated with senile plaque (SP) and neurofibrillary tangle (NFT) formation. Ferritin-stained microglia, Bielschowsky-stained neuritic plaques, and perikarya containing NFTs were counted in 8 young adults, 9 nondemented elderly adults, and 9 demented patients with AD. Microglial cell activation was moderately higher in elderly nondemented subjects. In AD there was a more striking activation in all sectors of the hippocampus. Most AMGs were distributed diffusely in neuropil and were not delimited to SPs or NFTs. Senile plaque counts were not linked with AMG counts within any sector. Neurofibrillary tangle counts were correlated significantly with AMG counts within one sector, the subiculum. When variations within and between sectors were factored out statistically, the burden of AMGs was correlated significantly with the burden of NFTs (r = 0.34; p < 0.005), but not SPs. Neuropathologic changes at the origin of the perforant pathway were correlated significantly with orthograde microglial cell activation in the termination field. These observations show that correlations between microglial cell activation and pathologic features of AD are only rarely significant. When significant linkage was present, it involved NFTs and not SPs, and depended on which sector of hippocampus was examined.

Adult↗
PubMed1994

Dynamics of the CA3 pyramidal neuron autoassociative memory network in the hippocampus.

A theory for the dynamics of sparse associative memory has been applied to the CA3 pyramidal recurrent network in the hippocampus. The CA3 region is modelled as a network of pyramidal neurons randomly connected through their recurrent collaterals. Both the elliptical spread of the axonal systems and the exponential decrease in connectivity with distance are taken into account in estimating the connection probabilities. Pyramidal neurons also receive connections from inhibitory interneurons which occur in large numbers throughout the network; these in turn receive inputs from other inhibitory interneurons and from pyramidal neurons. These inhibitory neurons are modelled as rapidly acting linear devices which produce outputs proportional to their inputs; they perform an important regulatory function in the setting of the membrane potentials of the pyramidal neurons. The probability of a neuron firing in a stored memory, which determines the average number of neurons active when a memory is recalled, can be set at will. Memories are stored at the recurrent collateral synapses using a two-valued Hebbian. Allowance is made in the theory both for the spatial correlations between the learned strengths of the recurrent collateral synapses and temporal correlations between the state of the network and these synaptic strengths. The recall of a memory begins with the firing of a set of CA3 pyramidal neurons that overlap with the memory to be recalled as well as the firing of a set of pyramidal neurons not in the memory to be recalled; the firing of both sets of neurons is probably induced by synapses formed on CA3 neurons by perforant pathway axons. The firing of different sets of pyramidal neurons then evolves by discrete synchronous steps. The CA3 recurrent network is shown to retrieve memories under specific conditions of the setting of the membrane potential of the pyramidal neurons by inhibitory interneurons. The adjustable parameters in the theory have been assigned values in accord with the known physiology of the CA3 region. Certain levels of overlap between the input and the memory to be retrieved must also be satisfied for almost complete retrieval. The number of memories which can be stored and retrieved without degradation is primarily a function of the number of active neurons when a memory is recalled and the degree of connectivity in the network. The inhomogeneity in the connectivity of the pyramidal cells improves both capacity and overlap of the final state with the memory.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗