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The hippocampal formation is a brain structure essential for higher-order cognitive functions. It has a complex anatomical organization and cellular composition, and hippocampal subregions have different properties and functional roles. In this study, we used SWATH-MS to determine whether the proteomes of hippocampus areas CA1 and CA3 can explain the commonalities or specificities of these subregions in basal conditions and after recognition memory. We show that the proteomes of areas CA1 and CA3 are largely different in basal conditions and that differential changes and dynamics in protein expression are induced in these areas after recognition of an object or object location. While changes are consistent across both recognition paradigms in area CA1, they are not in area CA3, suggesting distinct proteomic responses in areas CA1 and CA3 for memory formation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to stressful events can be differently perceived by individuals and can have persistent sequelae depending on the level of stress resilience or vulnerability of each person. The neural processes that underlie such clinically and socially important differences reside in the anatomical, functional, and molecular connectivity of the brain. Recent work has provided novel insight into some of the involved biological mechanisms that promises to help prevent and treat stress-related disorders. In this review, we focus on causal and mechanistic evidence implicating altered functions and connectivity of the neuroendocrine system, and of hippocampal, cortical, reward, and serotonergic circuits in the establishment and the maintenance of stress resilience and vulnerability. We also touch upon recent findings suggesting a role for epigenetic mechanisms and neurogenesis in these processes and briefly discuss promising avenues of future investigation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The molecular underpinnings of exploration and its link to learning and memory remain poorly understood. Here we show that inducible, modest overexpression of neuronal calcium sensor 1 (Ncs1) selectively in the adult murine dentate gyrus (DG) promotes a specific form of exploratory behavior. The mice also display a selective facilitation of long-term potentiation (LTP) in the medial perforant path and a selective enhancement in rapid-acquisition spatial memory, phenotypes that are reversed by direct application of a cell-permeant peptide (DNIP) designed to interfere with NCS-1 binding to the dopamine type-2 receptor (D2R). Moreover, the DNIP and the D2R-selective antagonist L-741,626 attenuated exploratory behavior, DG LTP, and spatial memory in control mice. These data demonstrate a role for NCS-1 and D2R in DG plasticity and provide insight for understanding how the DG contributes to the origin of exploration and spatial memory acquisition.

KAP1 is an essential cofactor of KRAB-zinc finger proteins, a family of vertebrate-specific epigenetic repressors of largely unknown functions encoded in the hundreds by the mouse and human genomes. Here, we report that KAP1 is expressed at high levels and necessary for KRAB-mediated repression in mature neurons of the mouse brain. Mice deleted for KAP1 in the adult forebrain exhibit heightened levels of anxiety-like and exploratory activity and stress-induced alterations in spatial learning and memory. In the hippocampus, a small number of genes are dysregulated, including some imprinted genes. Chromatin analyses of the promoters of two genes markedly upregulated in knockout mice reveal decreased histone 3 K9-trimethylation and increased histone 3 and histone 4 acetylation. We propose a model in which the tethering of KAP1-associated chromatin remodeling factors via KRAB-ZFPs epigenetically controls gene expression in the hippocampus, thereby conditioning responses to behavioral stress.

How conserved is sub-cellular compartmentalization across species and does it play a similar role? Here, two studies now demonstrate that buds in yeast and spines in mammalian neurons share many properties and suggest unexpected commonalities between simple and complex organisms.

Because activation of ERK1/2 MAP kinase (MAPK) is critical for hippocampus-dependent memory, there is considerable interest in mechanisms for regulation of MAPK during memory formation. Here we report that MAPK and CREB-mediated transcription are negatively regulated by SCOP (suprachiasmatic nucleus [SCN] circadian oscillatory protein) and that SCOP is proteolyzed by calpain when hippocampal neurons are stimulated by brain-derived neurotrophic factor (BDNF), KCl depolarization, or NMDA. Moreover, training for novel object memory decreases SCOP in the hippocampus. To determine if hippocampus-dependent memory is influenced by SCOP in vivo, we generated a transgenic mouse strain for the inducible overexpression of SCOP in the forebrain. Overexpression of SCOP completely blocked memory for novel objects. We conclude that degradation of SCOP by calpain contributes to activation of MAPK during memory formation.

The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.

Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two components: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (E-S coupling of LTP). We have used pharmacological and genetic approaches to address the molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of the Ca2+-sensitive phosphatase, calcineurin, prevents induction of E-S coupling without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA(A)-mediated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NMDA-dependent LTP mediates a coordinately regulated double function. It produces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enhancement of E-S coupling.

To obtain rapidly inducible and reversible expression of transgenes in the forebrain of the mouse, we have combined the reverse tetracycline-controlled transactivator (rtTA) system with the CaMKIIalpha promoter. We show that doxycycline induces maximal gene expression in neurons of the forebrain within 6 days and that this expression can be reversed by removal of doxycycline. Using calcineurin as a test transgene, we show that doxycycline-induced expression impairs both an intermediate form of LTP (I-LTP) in the hippocampus and the storage of spatial memory. The reversibility of the rtTA system in turn allowed us to examine the effects of the transgene on memory retrieval after normal storage had occurred. This examination suggests that retrieval requires some of the same molecular components required for storage.

To investigate the role of phosphatases in synaptic plasticity using genetic approaches, we generated transgenic mice that overexpress a truncated form of calcineurin under the control of the CaMKIIalpha promoter. Mice expressing this transgene show increased calcium-dependent phosphatase activity in the hippocampus. Physiological studies of these mice and parallel pharmacological experiments in wild-type mice reveal a novel, intermediate phase of LTP (I-LTP) in the CA1 region of the hippocampus. This intermediate phase differs from E-LTP by requiring multiple trains for induction and in being dependent on PKA. It differs from L-LTP in not requiring new protein synthesis. These data suggest that calcineurin acts as an inhibitory constraint on I-LTP that is relieved by PKA. This inhibitory constraint acts as a gate to regulate the synaptic induction of L-LTP.

To investigate the roles phosphatases play in hippocampal-dependent memory, we studied transgenic mice overexpressing a truncated form of calcineurin. These mice have normal short-term memory but defective long-term memory evident on both a spatial task and on a visual recognition task, providing genetic evidence for the role of the rodent hippocampus in spatial and nonspatial memory. The defect in long-term memory could be fully rescued by increasing the number of training trials, suggesting that the mice have the capacity for long-term memory. We next analyzed mice overexpressing calcineurin in a regulated manner and found the memory defect is reversible and not due to a developmental abnormality. Our behavioral results suggest that calcineurin has a role in the transition from short- to long-term memory, which correlates with a novel intermediate phase of LTP.

The use of standard genetic techniques, such as gene targeting and transgenesis, to study cognitive function in adult animals suffers from the limitations that the gene under study is often altered in many brain regions, and that this alteration is present during the entire developmental history of the animal. Furthermore, to relate cognitive defects to neuronal mechanisms of memory, studies have relied on examining long-term potentiation - an artificially induced form of synaptic plasticity. Recent technical advances allow the expression of a genetic alteration in mice to be restricted both anatomically and temporally, making possible a more precise examination of the role of various forms of synaptic plasticity, such as long-term potentiation and long-term depression, in memory formation. Recordings from so-called 'place cells' -hippocampal cells that encode spatial location -in freely moving, genetically modified mice have further advanced our understanding of how the actual cellular representation of space is influenced by genetic alterations that affect long-term potentiation.