Long-term potentiation induced by physiologically relevant stimulus patterns

Single pulse stimuli were delivered to the Schaffer collaterals in the in vitro hippocampal slice preparation. Local application of bicuculline to the CA3 region resulted in a series of population cell bursts in CA3, resembling the neuronal patterns which occur in the normal, freely moving rat during hippocampal sharp waves. These bicuculline-induced cell bursts in CA3 resulted in long-term potentiation (LTP) of the CA1 response. These findings suggest that the naturally occurring hippocampal sharp waves may reflect events analogous to artificially induced LTP.     

Hippocampal mossy fiber distribution and long-term potentiation in two inbred mouse strains

We studied long-term potentiation in the inbred mouse strains DBA/2 and C3H/He known to be different in both hippocampal mossy fiber distribution and several aspects of learning. Tetanic stimulation of mossy fibers resulted in a significantly stronger increase of the population spike amplitude in the CA3 pyramidal cell layer of C3H mice. This result suggests that the extent of the CA3 hippocampal mossy fiber projection correlates with synaptic efficacy in mice.     

The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxtine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal thytmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occuring in close correlation with Type 1 behaviors (postular changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also thought to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior.Most rats developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methylsergide or benserazide. Metergoline (and methylsergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.     

Intracerebroventricular norepinephrine potentiation of the perforant path-evoked potential in dentate gyrus of anesthetized and awake rats: A role for both α- and β-adrenoceptor activation

Norepinephrine (NE) applied iontophoretically to the dentate gyrus in vivo, and bath applied to hippocampal slices in vitro, produces potentiation of the perforant path-evoked potential. β-receptors mediate exogenous NE potentiation in vitro, while α-receptors are implicated in exogenous effects in vivo. The present study uses intracerebroventricular (i.c.v.) NE to mimic in vitro bath conditions in vivo. Short-term NE potentiation was reliably seen with 10 μg [±] NE in 2 μl of 0.9% saline i.c.v. Long-term potentiation occurred with higher doses of NE. The β-agonist isoproterenol and the α-agonist phenylephrine also produced potentiation. Long-term effects were common with isoproterenol. The β-antagonist metoprolol and the α-antagonist phentolamine attenuated NE potentiation. The results suggest that both α- and β-receptors could play a role in NE potentiation in dentate gyrus in vivo. In awake animals, 10 μg NE i.c.v. reproduced the potentiation pattern seen in anesthetized rats. NE potentiation in awake rats was independent of behavioral variation.     

Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment

Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characterized. Insulin treatment was commenced at the onset of diabetes in a prevention experiment, and 10 weeks after diabetes induction in a reversal experiment. After 10 weeks of treatment, insulin-treated diabetic rats, untreated diabetic rats and non-diabetic controls were tested in a spatial version of the Morris water maze. Next, hippocampal long-term potentiation (LTP) was measured in vitro. To further characterize the effects of diabetes on water maze learning, a separate group of rats was pre-trained in a non-spatial version of the maze, prior to exposure to the spatial version. Both water maze learning and hippocampal LTP were impaired in diabetic rats. Insulin treatment commenced at the onset of diabetes prevented these impairments. In the reversal experiment, insulin treatment failed to reverse established deficits in maze learning and restored LTP only partially. Non-spatial pre-training abolished the performance deficit of diabetic rats in the spatial version of the maze. It is concluded that insulin treatment may prevent but not reverse deficits in water maze learning and LTP in streptozotocin-diabetic rats. The pre-training experiment suggests that the performance deficit of diabetic rats in the spatial version of the water maze is related to difficulties in learning the procedures of the maze rather than to impairments of spatial learning.     

Two types of neuroplasticities in the kindling phenomenon: effects of chronic MK-801 and methamphetamine

Using the low-frequency kindling technique, we studied the effects of chronic MK-801 and chronic methamphetamine (MAP) administration on hippocampal kindling seizure development. In experiment 1, MK-801 (0.05, 0.1 mg/kg i.p.) was administered 2 h before each electrical stimulation until kindling developed into stage-3 seizure. In experiment 2, we started daily electrical stimulations two weeks after the last injection of chronic MAP administration (6 mg/kg/day, 14 days). The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling; the kindling rates for stage 3 and stage 5 seizures; seizure parameters at the completion of kindling of the drug-treated groups were recorded and compared to the values of each saline-treated control group. Our result showed that MK-801 administration prior to each electrical stimulation selectively and significantly increased PNT in the initial stage of kindling without affecting other seizure parameters. Chronic pretreatment of MAP caused a selective and significant decrease of PNT of the first two stimulations in the kindling process. Taken together with the previous studies, these results suggest that long-term potentiation plays an important role in the development of the excitability of seizure focus but not of the induced seizure's propagation in the hippocampal kindling phenomenon. Clinically MK-801 seems to be a more efficacious drug in preventing the induction of seizures than in suppressing the acquired seizures.     

Human Hippocampal Seizure Spread Studied by Depth and Subdural Recording: The Hippocampal Commissure

Eleven patients had seizures with unilateral temporal lobe onset recorded with simultaneous bilateral medial temporal depth electrodes and neocortical (subdural) electrodes at least on the side of seizure onset. Of a total of 55 seizures, four had simultaneous onset in neocortex and hippocampus, and 51 had onset in unilateral hippocampus. None originated solely in temporal neocortex. Three reproducible patterns of seizure spread from hippocampus were defined in which seizures spread initially to ipsilateral neocortex (32 seizures), spread first to contralateral hippocampus (13 seizures), or spread simultaneously to ipsilateral neocortex and contralateral hippocampus. Although the region of hippocampus in which seizures arose was constant, patterns of spread sometimes varied in the same patient. When contralateral neocortical involvement occurred, it was after or with contralateral hippocampus but never before. These results suggest the existence of an operational hippocampal commissure in humans.     

Pioneering concepts in epileptology: The cerebral dysrhythmia of Frederic Gibbs (1903-92) and William Lennox (1884-1960)

The development of the electroencephalogram and its use in the study of epilepsy supplied the research team of William Lennox and Frederic (Frederick) Gibbs at Harvard University with an entirely new method of studying the epileptic activity of the brain. The abnormal activity, thought to be a “dysrhythmia”, seemed to indicate a central role for inheritance in this condition, and there seemed a more considerable penetration of inheritable epileptic tendency in the community than at first thought. Lennox, who had a long-held interest in eugenics, felt that further study was needed and this he undertook in his famous “Twin Series” exploring epilepsy in identical and non-identical twin pairs. Frederic and Erna Gibbs, however, went on to study the electrical activity accompanying various clinical seizure types. These were the early days of electroencephalography, and mistaken over-emphasis given to various forms of non-specific slower components introduced conceptual errors in both areas of research. However, the overall results of this pioneering research provided very significant advances in epileptology.     

In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic Kv1.1α knockout mice

The ketogenic diet (KD) is an effective therapy for pediatric refractory epilepsies; however, whether the KD changes the pathologic network oscillations generated by an epileptic brain remains unknown. We have reported that hippocampal CA3 regions of epileptic Kv1.1α knockout (KO) mice generate pathologic sharp waves (SPWs) and high‐frequency oscillations (HFOs) that have higher incidence, longer duration, and fast ripples compared to wild‐type (WT). Synaptic activity of hyperexcitable KO mossy fibers significantly decreased CA3 principal cell spike‐timing reliability, which contributed to this network pathology. In addition, we have demonstrated that the KD reduces seizures by 75% in KO mice. Here, we determined whether 10‐ to 14‐day in vivo KD treatment exerts disease‐modifying effects that alter the spontaneous SPW‐HFO complexes generated by the hippocampal CA3 region of KO mice in vitro using extracellular multielectrode array recordings. We found that KD treatment significantly attenuated the pathologic features of KO SPWs and ripples and reduced the incidence of fast ripples. The KD also improved spike‐timing reliability of KO CA3 principal cells, decreased mossy fiber excitability, increased mossy fiber‐CA3 paired‐pulse ratios, and reduced coupling of field excitatory postsynaptic potentials and population spikes in the CA3 region. Collectively, these data indicate that KD treatment modulates CA3‐generated pathologic oscillations by dampening hyperactive mossy fiber synapses. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Hippocampal activity, olfaction, and sniffing: an olfactory input to the dentate gyrus

Experiments in freely moving rats showed that olfactory stimuli elicit a burst of rhythmical 15-30 Hz waves in or near the hilus of the dentate gyrus but not in adjacent regions of CA1. This fast wave burst is not elicited by visual, auditory, or somatosensory inputs and is not related to motor activity. Electrical stimulation of the olfactory bulb evokes a complex potential in the hilus of the dentate gyrus but not in adjacent regions of CA1. Experiments making use of wave-triggered averaging demonstrated that there is a degree of phase-locking between (a) hippocampal RSA and sniffing or other respiratory patterns, (b) hippocampal RSA and the initiation of jumping, and (c) respiration and the initiation of jumping. An early hypothesis that the hippocampus and dentate gyrus are part of an olfacto-motor mechanism may merit re-examination.     

Calcium-induced long-term potentiation in the hippocampal slice: Characterization of the time course and conditions

A transient increase in extracellular calcium concentration causes a long-lasting enhancement of radiatum fibers evoked excitatory postsynaptic potential and population spike responses of CA1 pyramidal neurons which resembles long-term potentiation (LTP). The duration of this potentiation is much longer than described previously and is probably limited by the survival of the preparation itself (greater than 8 hr). Therefore, Ca-induced LTP can be used for the investigation of a postulated late phase of LTP. Ca effects were activity-independent, since the subsequently evoked responses were facilitated even when the presynaptic fibers were not concurrently stimulated during or immediately after superfusion with the high Ca medium. In contrast, if too frequent testing of the synaptic input was done during the high Ca pulse, a short lasting depression instead of potentiation was observed. A lower extracellular magnesium concentration in the standard medium (1.3 instead of 2.0 mM MgSO4) prevents the potentiation of the EPSP at least for the first few hours. Presumably, both tetanus- and Ca-induced LTP share some common mechanisms, since an additional tetanization after Ca induction was not followed by an additional LTP. Compared to the potentiation following tetanization, the Ca-induced LTP was, however, not accompanied by a potentiation of the EPSP/spike ratio within the range of the population spike threshold intensity.     

Long-term potentiation: Persisting problems and recent results

In this paper we discuss recent experimental results pertinent to three unresolved issues regarding the long-term potentiation (LTP) effect: the nature of its enduring substrates, the biochemical mechanisms that produce it, and its potential role in memory. LTP appears to be triggered by a postsynaptic influx of calcium and is associated with alterations in the shape of dendritic spines and probably the formation of new synapses. We discuss the possibility that morphological reorganization also modifies membrane surface chemistry of synaptic elements. Evidence is presented that LTP is not associated with changes in presynaptic calcium currents. Activation of protein kinase C is shown to be insufficient for the induction of LTP, although it may play a modulatory role. The hypothesis that activation of a calcium-sensitive protease (calpain) is pivotal to the establishment of LTP is supported by experiments showing that a calpain inhibitor, leupeptin, blocks LTP. Furthermore, activation of NMDA receptors, an event implicated in LTP induction, is accompanied by calcium-sensitive proteolysis of spectrin, a major dendritic cytoskeletal protein. The finding that stimulation patterns designed to mimic naturally-occurring cell discharge patterns are highly effective for LTP induction greatly strengthens the hypothesis that LTP actually occurs during the encoding of information in cortical systems. Potential contributions of LTP to learning are explored using computer simulations of a simple cortical network.     

Long-term potentiation persistence greater in C57BL/6 than DBA/2 mice: Predicted on basis of protein kinase C levels and learning performance

The gamma isoform of protein kinase C (γ-PKC) activity is elevated and learning is superior in the inbred C57BL/6 mouse when compared to the DBA/2 mouse strain. Given the proposed link between PKC and long-term potentiation (LTP) on the one hand and PKC and learning on the other, it was predicted that LTP persistence would be greater in C57BL/6 mouse. When suprathreshold levels of tetanic stimulation were used, similar persistent LTP was observed in both C57BL/6 and DBA/2 strains. However, when tetanus was at threshold, the response in DBA/2 mice decayed to baseline in 30 min. similar to short-term potentiation (STP). Using this same paradigm with C57BL/6 mice. LTP persisted for 4 h, the longest time tested. The time course of the results parallels those observed in rat when phorbol ester, a potent PKC activator, converts STP to LTP. The present findings thus confirm the predicted difference between the two mouse strains. Moreover, the present findings are consistent with a role for γ-PKC in LTP. Since such results call attention to the need for γ-PKC interventive procedures, the relative utility of current PKC inhibitors, null mutants and antisense methods are discussed.     

Spontaneous neural activity of the anterodorsal lobe and entopeduncular nucleus in adult zebrafish: a putative homologue of hippocampal sharp waves

Spontaneous neural activity is instrumental in the formation and maintenance of neural circuits that govern behavior. In mammals, spontaneous activity is observed in the spinal cord, brainstem, diencephalon, and neocortex, and has been most extensively studied in the hippocampus. Using whole-brain in vitro recordings we establish the presence of spontaneous activity in two regions of the zebrafish telenchephalon: the entopeduncular nucleus (EN) and the anterodorsal lobe (ADL). The ADL is part of the lateral telencephalic pallium, an area hypothesized to be functionally equivalent to the mammalian hippocampus. In contrast, the EN has been hypothesized to be equivalent to the mammalian basal ganglia. The observed spontaneous activity is GABA modulated, sensitive to glutamate and chloride transporter antagonists, and is abolished by sodium pump blockers; moreover, the spontaneous activity in the ADL is a slow multiband event (∼100 ms) characterized by an embedded fast ripple wave (∼150-180 Hz). Thus, the spontaneous activity in the ADL shares physiological features of hippocampal sharp waves in rodents. We suggest that this spontaneous activity is important for the formation and maintenance of neural circuits in zebrafish and argue that applying techniques unique to the fish may open novel routes to understand the function of spontaneous activity in mammals.     

Epileptic encephalopathy with continuous spikes and waves during sleep in children with shunted hydrocephalus: a study of nine cases

Purpose: We present a series of nine patients with early‐onset hydrocephalus who had seizures and continuous spikes and waves during slow sleep (CSWS) associated with neurocognitive and motor deterioration. Methods: Six boys and three girls aged 9–16 years (mean 11.3 years) were studied. [Correction added after online publication 12‐Apr‐2008: Number of girls and boys has been updated.] All patients underwent clinical examinations, electroencephalographic evaluations, neuroradiological imaging and neuropsychological assessment at first examination. Antiepileptic drugs (AEDs) were given in all cases and changed according to clinical and EEG evolution. Results: Onset of epilepsy occurred from age 8 to 60 months (mean 19.6 months and median 14 months) with focal seizures with or without secondary generalized tonic–clonic seizures. Between ages 6 and 13 years (mean 10.4 years and median 8 years), hyperkinesia, aggressiveness, and poor socialization appeared in all nine cases. Reduced attention span, deterioration of language, and temporospatial disorientation were found in three of them. Negative myoclonus was found in two patients. The EEG showed CSWS. Response to change in treatment was good in all patients. None of the patients had relapses, seven of them have remained seizure free, and two continued having sporadic focal motor seizures during 2–5 years (mean 3 years) of follow‐up. Conclusion: In children with early‐onset hydrocephalus, particularly with behavioral and language disturbances and/or motor deterioration, CSWS should be considered. Periodic EEG recordings during sleep should be done in these children. The early identification of this particular electroclinical picture is crucial to start adequate treatment to avoid progressive cognitive deterioration.     

LTP-associated EPSP/spike dissociation in the dentate gyrus: GABAergic and non-GABAergic components

The induction of long-term potentiation (LTP) in the dentate gyrus (DG) leads to a change in the firing characteristics of the dentate granule cells. This phenomenon, termed EPSP/spike dissociation, is seen in field potential studies as a shift to the left of the E-S curve, in which population spike amplitude is plotted against pEPSP slope at various stimulus intensities. It has been suggested that EPSP/spike dissociation reflects a decrease in feed-forward inhibition. To test this hypothesis, we blocked GABA-A neurotransmission in a circumscribed area of the DG in urethane-anaesthetized rats by inserting a micropipette filled with 8 mM bibuculline methiodide in saline. We then recorded E-S curves from 9 such electrodes and from 8 control electrodes before and after inducing LTP in the perforant path. Bicuculline prevented the LTP-associated leftward shift of the E-S curves. Instead, the E-S curve showed a consistent shift to the right at the bicuculline sites after LTP, reflecting potentiation of the pEPSP without corresponding increases in the population spike amplitude. The results indicate that the EPSP/spike relationship is controlled largely by GABAergic input, and that potentiation of the population spike in the DG depends largely on a change in the EPSP/spike relationship.     

Issues & opinions: Single muscle fiber discharges (insertional activity,end-plate potentials,positive sharp waves,and fibrillation potentials): A unifying proposal

The exact origin and precise morphologic explanation of positive sharp waves (PSWs) are presently lacking. Observing normal needle electromyographic insertional activity reveals two types of waveforms: (1) biphasic negative/positive spikes, and (2) positive spikes followed by a small negative phase. In the end-plate region, it is possible to occasionally observe a biphasic end-plate spike transform into a monophasic positive end-plate waveform. It is postulated that this waveform is simply a form of intracellular recording for the biphasic end-plate spike or a form of extracellularly recorded but blocked single muscle fiber discharge. Similarly, the observed monophasic positive insertional activity may be an intracellularly recorded single muscle fiber discharge or a blocked extracellular discharge originating about the needle electrode. Applying this reasoning to PSWs suggests that they may also be an intracellular recording of a fibrillation potential, or needle-induced extracellular blocked local single muscle fiber discharge. This unifying concept is applied to various clinical situations purported to demonstrate “different” types of PSWs. © 1996 John Wiley & Sons, Inc.     

Vortices in brain activity: Their mechanism and significance for perception

Brains interface with the world through perception. The process extracts information from microscopic sensory inputs and incorporates it into the mesoscopic memory store for retrieval in recognition. The process requires creation of spatiotemporal patterns of neural activity. The construction is done through phase transitions in cortical populations that condense the background activity through spontaneous symmetry breaking. Large-scale interactions create fields of synaptically driven activity that is observed by measuring brain waves (electrocorticogram, ECoG) and evaluated by constructing a mesoscopic vectorial order parameter as follows. The negative feedback among excitatory and inhibitory neurons creates spatially and spectrally distributed gamma oscillations (20–80 Hz) in the background activity. Band pass filtering reveals beats in ECoG log analytic power. In some beats that recur at theta rates (3–7 Hz), the order parameter transiently approaches zero, giving a null spike in which the microscopic activity is uniformly disordered (symmetric). A phase transition that is manifested in an analytic phase discontinuity breaks the symmetry. As the null spike terminates, the resurgent order parameter imposes mesoscopic order seen in spatial patterns of ECoG amplitude modulation (AM) that actualize and update the memory of a stimulus. Read-out is through a divergent/convergent projection that performs on cortical output an irreversible spatiotemporal integral transformation. The ECoG reveals a conic phase gradient that accompanies an AM pattern. The phase cone manifests a vortex, which is initiated by the null spike, and which is inferred to help stabilize and prolong its accompanying AM pattern that might otherwise be rapidly degraded by the turbulent neural noise from which it emerges.     

Spontaneous depolarization wave in the mouse embryo: origin and large-scale propagation over the CNS identified with voltage-sensitive dye imaging

Spontaneous embryonic movements, called embryonic motility, are produced by correlated spontaneous activity in the cranial and spinal nerves, which is driven by brainstem and spinal networks. Using optical imaging with a voltage-sensitive dye, we have revealed previously that this correlated activity is a widely propagating wave of neural depolarization, which we termed the depolarization wave. We have observed in the chick and rat embryos that the activity spread over an extensive region of the CNS, including the spinal cord, hindbrain, cerebellum, midbrain and forebrain. One important consideration is whether a depolarization wave with similar characteristics occurs in other species, especially in different mammals. Here, we provide evidence for the existence of the depolarization wave in the mouse embryo by showing that the widely propagating wave appeared independently of the localized spontaneous activity detected previously with Ca(2+) imaging. Furthermore, we mapped the origin of the depolarization wave and revealed that the wave generator moved from the rostral spinal cord to the caudal cord as development proceeded, and was later replaced with mature rhythmogenerators. The present study, together with an accompanying paper that describes pharmacological properties of the mouse depolarization wave, shows that a synchronized wave with common characteristics is expressed in different species, suggesting fundamental roles in neural development.