Serge Laroche

A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories

The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

New neurons in the dentate gyrus are involved in the expression of enhanced long‐term memory following environmental enrichment

Although thousands of new neurons are continuously produced in the dentate gyrus of rodents each day, the function of these newborn cells remains unclear. An increasing number of reports have provided correlational evidence that adult hippocampal neurogenesis is involved in learning and memory. Exposure of animals to an enriched environment leads to improvement of performance in several learning tasks and enhances neurogenesis specifically in the hippocampus. These data raise the question of whether new neurons participate in memory improvement induced by enrichment. To address this issue, we have examined whether the increase in the number of surviving adult‐generated cells following environmental enrichment contributes to improved memory function. To this end, neurogenesis was substantially reduced throughout the environmental enrichment period using the antimitotic agent methylazoxymethanol acetate (MAM). Recognition memory performance of MAM‐treated enriched rats was evaluated in a novel object recognition task and compared with that of naïve and nontreated enriched rats. Injections of 5‐bromo‐2′‐deoxyuridine were used to label dividing cells, together with double immunofluorescent labelling using glial or neuronal cell‐specific markers. We found that enrichment led to improved long‐term recognition memory and increased hippocampal neurogenesis, and that MAM treatment during environmental enrichment completely prevented both the increase in neurogenesis and enrichment‐induced long‐term memory improvement. These results establish that newborn cells in the dentate gyrus contribute to the expression of the promnesic effects of behavioural enrichment, and they provide further support for the idea that adult‐generated neurons participate in modulating memory function.

Plasticity at hippocampal to prefrontal cortex synapses: dual roles in working memory and consolidation.

The involvement of the hippocampus and the prefrontal cortex in cognitive processes and particularly in learning and memory has been known for a long time. However, the specific role of the projection which connects these two structures has remained elusive. The existence of a direct monosynaptic pathway from the ventral CA1 region of the hippocampus and subiculum to specific areas of the prefrontal cortex provides a useful model for conceptualizing the functional operations of hippocampal‐prefrontal cortex communication in learning and memory. It is known now that hippocampal to prefrontal cortex synapses are modifiable synapses and can express different forms of plasticity, including long‐term potentiation, long‐term depression, and depotentiation. Here we review these findings and focus on recent studies that start to relate synaptic plasticity in the hippocampo‐prefrontal cortex pathway to two specific aspects of learning and memory, i.e., the consolidation of information and working memory. The available evidence suggests that functional interactions between the hippocampus and prefrontal cortex in cognition and memory are more complex than previously anticipated, with the possibility for bidirectional regulation of synaptic strength as a function of the specific demands of tasks. Hippocampus 10:438–446, 2000

A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval.

Recent research has revived interest in the possibility that previously consolidated memories need to reconsolidate when recalled to return to accessible long-term memory. Evidence suggests that both consolidation and reconsolidation of certain types of memory require protein synthesis, but whether similar molecular mechanisms are involved remains unclear. Here, we explore whether zif268, an activity-dependent inducible immediate early gene (IEG) required for consolidation of new memories, is also recruited for reconsolidation of recognition memory following reactivation. We show that when a consolidated memory for objects is recalled, zif268 mutant mice are impaired in further long-term but not short-term recognition memory. The impairment is specific to reactivation with the previously memorized objects in the relevant context, occurs in delayed recall, and does not recover over several days. These findings indicate that IEG-mediated transcriptional regulation in neurons is one common molecular mechanism for the storage of newly formed and reactivated recognition memories.

Long-Term Potentiation Enhances Neurogenesis in the Adult Dentate Gyrus

Activity-dependent synaptic plasticity and neurogenesis are two forms of brain plasticity that can participate in functional remodeling of neural networks during the formation of memories. We examined whether long-term potentiation (LTP) of excitatory synaptic transmission, a well characterized form of synaptic plasticity believed to play a critical role in memory formation, can regulate the rate of neurogenesis in the adult rat dentate gyrus in vivo. We first show that induction of LTP at medial perforant path–granule cell synapses stimulates the proliferation of progenitor cells in the dentate gyrus with a consequential long-term persistence of a larger population of surviving newborn cells. Using protocols to examine the effect of LTP on survival, we next show that LTP induction promotes survival of 1- to 2-week-old dentate granule cells. In no case did LTP appear to affect neuronal differentiation. Finally, we show that LTP induces expression of the plasticity-related transcription factor Zif268 in a substantial fraction of 2-week-old but not 1-week-old neurons, suggesting the prosurvival effect of LTP can be observed in the absence of LTP-mediated Zif268 induction in newborn cells. Our results indicate that electrically induced LTP in the dentate gyrus in vivo provides a cellular/molecular environment that favors both proliferation and survival of adult-generated neurons.

How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning

The immediate early genes (IEGs) are activated rapidly and transiently in response to a multitude of stimuli. The zif268 belongs to a category of regulatory IEGs that activate downstream target genes and is considered to be a triggering mechanism to activate the genomic response in neurons. Several studies have shown that zif268 mRNA is upregulated during different forms of associative learning, and following tetanic stimulation that induces long-lasting LTP. To date, there is a general consensus that zif268 activation may constitute a critical mechanism for the encoding of long-lasting memories, however this is based on relatively few studies. Given the fact that zif268 can be activated by a number of different types of stimuli, it becomes important to determine exactly how it may be implicated in memory. Examination of the current literature suggests that zif268 is necessary in the processing of several types of memory, however, it is not entirely clear what aspects of memory zif268 may be implicated in. Here, we review the existing literature and emphasise that understanding the signalling pathways that lead to activation of the IEGs and the downstream targets of these genes will advance our understanding of how functional activation of zif268 may be implicated in processing long-term memories.

Long-term potentiation in the prefrontal cortex following stimulation of the hippocampal CA1/subicular region

We have examined single cell activity and field potentials in the prelimbic area of the prefrontal cortex of the rat to electrical stimulation of the CA1/subicular region of the temporal hippocampus. Excitatory unit responses were found in 50 out of 120 neurons recorded in the prelimbic area. Paired-pulse facilitation was found for both single cell responses and field potentials. High-frequency, tetanic stimulation of the temporal hippocampus produced a significant and persistent potentiation of prelimbic field potentials. The evidence suggests that the direct pathway from the temporal hippocampus to the prelimbic area of the prefrontal cortex in the rat is excitatory and can undergo long-term potentiation (LTP).

Adult Hippocampal Neurogenesis, Synaptic Plasticity and Memory: Facts and Hypotheses

The demonstration that progenitor cells in regions of the adult mammalian brain such as the dentate gyrus of the hippocampus can undergo mitosis and generate new cells that differentiate into functionally integrated neurons throughout life has marked a new era in neuroscience. In recent years, a wide range of investigations has been directed at understanding the physiological mechanisms and functional relevance of this form of brain plasticity. Our current knowledge of adult hippocampal neurogenesis indicates that the production of new cells in the brain follows a multi-step process during which newborn cells are submitted to various regulatory factors that influence cell proliferation, maturation, fate determination and survival. As details of the dynamics of morphological maturation and functional integration of newborn neurons in corticohippocampal circuits have become clearer, an increasing number of studies have examined how environmental and/or behavioural factors can modulate neurogenesis and affect hippocampal-dependent learning and memory. In this article we present an overview of recent literature that relates neurogenesis to hippocampal function on the basis of correlative studies investigating the modulation of neurogenesis by learning and behavioural experience, and the consequences of the loss of hippocampal neurogenesis for memory function. We also highlight experimental evidence that immature neurons exhibit unique electrophysiological characteristics and therefore may constitute a specific cell population particularly inclined to undergo activity-dependent plasticity. Moreover, we review recent work that reveals an unsuspected mechanistic link between synaptic plasticity and the proliferation and survival of new hippocampal neurons. From the present background of research, we argue that the incorporation of functional adult-generated neurons into existing neural networks provides a higher capacity for plasticity, which may favour the encoding and storage of certain types of memories. Depending on their birth date and maturation stage, new neurons might be implicated in the encoding/storage process of the task at hand or may help future learning experience. Finally, we highlight critical issues to be addressed in order to decipher the exact contribution of newly generated neurons to cognitive functions.

Generation of Aggregated β-Amyloid in the Rat Hippocampus Impairs Synaptic Transmission and Plasticity and Causes Memory Deficits

We injected a combination of the β-amyloids (Aβs) Aβ40 and Aβ43 to “seed” formation of amyloid deposits in the dorsal dentate gyrus of rats in vivo, on the basis of a theory of Jarrett and Landsbury (1993). Rats were tested on several different learning tasks, and synaptic transmission and plasticity were assessedin vivo. Between 7 and 16 weeks after injection, we found aggregated amyloid material, reactive astrocytosis, microgliosis, and cell loss around the sites of injection. Rats were impaired specifically in working memory type tasks in accordance with the type of memory deficit observed in the early stages of Alzheimers disease. Synaptic transmission and long-term potentiation, a candidate cellular mechanism for memory, were severely impaired in vivo. Injections of the same dose of fragments individually did not induce these effects. These findings suggest that aggregated amyloid material induces cognitive deficits similar to those observed in the early phases of Alzheimers disease via an alteration in neuronal transmission and plasticity.

Signalling mechanisms mediated by the phosphoinositide 3‐kinase/Akt cascade in synaptic plasticity and memory in the rat

The phosphoinositide 3‐kinase (PI3K)/Akt signalling cascade has classically been implicated in promoting cell survival but more recently has been shown to regulate a number of other cellular functions. In particular, studies have suggested that PI3K contributes to mechanisms associated with synaptic plasticity and memory processes but the function of this cascade in forms of synaptic plasticity, such as long‐term potentiation, remains controversial and the PI3K substrates which mediate these effects are poorly understood. Here we report that the PI3K inhibitor LY294002 infused i.c.v. in vivo blocked maintenance of long‐term potentiation induced in the dentate gyrus with a single tetanus to the perforant path but not with repeated tetani. This pattern of stimulation led to rapid and transient phosphorylation of the PI3K substrate Akt at Ser473 but not at Thr308. Functional readout of partial activation of Akt was demonstrated by an increase in phosphorylation of two downstream substrates, Forkhead (FKHR) and mammalian target of rapamycin (mTOR), in a delayed and prolonged manner at Akt‐specific phosphorylation sites. LY294002 blocked phosphorylation of Akt and the prolonged phosphorylation of FKHR and mTOR but did not impair long‐term potentiation‐induced phosphorylation of extracellular receptor kinase. In addition, the same i.c.v. concentration of LY294002 impaired long‐term consolidation of recognition memory but not short‐term recognition memory or spatial learning and repeated training in the recognition memory task overcame the deficit in consolidation. These results suggest that activation of the PI3K/Akt pathway may contribute to the mechanisms of synaptic plasticity and memory consolidation by promoting cell survival via FKHR and protein synthesis via mTOR. Importantly, only partial activation of Akt at its Ser473 residue was necessary to mediate these effects.