Behavioral characterization of Capn15 conditional knockout mice.

Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, which has an important role in development. Loss of Capn15 in mice leads to developmental eye anomalies and volumetric changes in the brain. Human individuals with biallelic variants in CAPN15 have developmental delay, neurodevelopmental disorders, as well as congenital malformations.

A novel stress-based intervention reduces cigarette use in non-treatment seeking smokers.

Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessation aids show only modest efficacy, new interventions are needed. Given the evidence that stress is a potent trigger for smoking, the present randomized clinical trial tested whether stress could augment the effects of a memory updating (retrieval-extinction) intervention.

Memory Destabilization and Reconsolidation Dynamically Regulate the PKMζ Maintenance Mechanism.

Useful memory must balance between stability and malleability. This puts effective memory storage at odds with plasticity processes, such as reconsolidation. What becomes of memory maintenance processes during synaptic plasticity is unknown.

Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2.

Translational control plays a key role in regulation of neuronal activity and behavior. Deletion of the translational repressor 4E-BP2 in mice alters excitatory and inhibitory synaptic functions, engendering autistic-like behaviors. The contribution of 4E-BP2-dependent translational control in excitatory and inhibitory neurons and astrocytic cells to these behaviors remains unknown.

Cortico-hippocampal Schemas Enable NMDAR-Independent Fear Conditioning in Rats.

The neurobiology of memory formation has been studied primarily in experimentally naive animals, but the majority of learning unfolds on a background of prior experience. Considerable evidence now indicates that the brain processes initial and subsequent learning differently. In rodents, a first instance of contextual fear conditioning requires NMDA receptor (NMDAR) activation in the dorsal hippocampus, but subsequent conditioning to another context does not.

Differential role of the anterior and intralaminar/lateral thalamic nuclei in systems consolidation and reconsolidation.

The anterior thalamic nuclei (ATN) and the intralaminar/lateral thalamic nuclei (ILN/LT) play different roles in memory processes. The ATN are believed to be part of an extended hippocampal system, and the ILN/LT have strong connections with the medial prefrontal cortex. It was shown that the ILN/LT are involved in systems consolidation.

Metformin ameliorates core deficits in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1 mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9.

The X-linked inhibitor of apoptosis regulates long-term depression and learning rate.

Hippocampal long-term depression (LTD) is an active form of synaptic plasticity that is necessary for consolidation of spatial memory, contextual fear memory, and novelty acquisition. Recent studies have shown that caspases (CASPs) play an important role in NMDA receptor-dependent LTD and are involved in postsynaptic remodeling and synaptic maturation. In the present study, we examined the role of X-linked inhibitor of apoptosis (XIAP), a putative endogenous CASP inhibitor, in synaptic plasticity in the hippocampus.

Memory retrieval requires ongoing protein synthesis and NMDA receptor activity-mediated AMPA receptor trafficking.

Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synthesis, memory retrieval has long been considered a passive readout of previously established plasticity. However, previous findings suggest that memory retrieval may be more dynamic than previously thought. This study therefore aimed at investigating the molecular mechanisms underlying memory retrieval in the rat.

Pharmacological brake-release of mRNA translation enhances cognitive memory.

Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR).

Control of synaptic plasticity and memory via suppression of poly(A)-binding protein.

Control of protein synthesis is critical for synaptic plasticity and memory formation. However, the molecular mechanisms linking neuronal activity to activation of mRNA translation are not fully understood. Here, we report that the translational repressor poly(A)-binding protein (PABP)-interacting protein 2A (PAIP2A), an inhibitor of PABP, is rapidly proteolyzed by calpains in stimulated neurons and following training for contextual memory.

Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder.

Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches.

Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect.

Reducing reconsolidation of reactivated traumatic memories may offer a novel pharmacological treatment for posttraumatic stress disorder (PTSD). Preclinical research is needed to identify candidate drugs. We evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats.

PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking.

The maintenance of long-term memory in hippocampus, neocortex and amygdala requires the persistent action of the atypical protein kinase C isoform, protein kinase Mzeta (PKMzeta). We found that inactivating PKMzeta in the amygdala impaired fear memory in rats and that the extent of the impairment was positively correlated with a decrease in postsynaptic GluR2. Blocking the GluR2-dependent removal of postsynaptic AMPA receptors abolished the behavioral impairment caused by PKMzeta inhibition and the associated decrease in postsynaptic GluR2 expression, which correlated with performance.

eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory.

The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning.

NMDA receptors are critical for unleashing consolidated auditory fear memories.

Memories are dynamic and can change when recalled. The process that returns memories to a labile state during remembering is unclear. We found that the presence of NMDA, but not AMPA, receptor antagonists in the amygdala prior to recall prevented the consolidated fear memory from returning to a labile state.