Insulin-like growth factor 2 (IGF-2) rescues social deficits in NLG3 mouse model of ASDs.

Autism spectrum disorders (ASDs) comprise developmental disabilities characterized by impairments of social interaction and repetitive behavior, often associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASDs symptomatology; thus, identifying novel therapies is urgently needed. Here, we used the Neuroligin 3 knockout mouse (NLG3), a model that recapitulates the social deficits reported in ASDs patients, to test the effects of systemic administration of IGF-2, a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer.

Neuronal activity drives IGF2 expression from pericytes to form long-term memory.

Investigations of memory mechanisms have been, thus far, neuron centric, despite the brain comprising diverse cell types. Using rats and mice, we assessed the cell-type-specific contribution of hippocampal insulin-like growth factor 2 (IGF2), a polypeptide regulated by learning and required for long-term memory formation. The highest level of hippocampal IGF2 was detected in pericytes, the multi-functional mural cells of the microvessels that regulate blood flow, vessel formation, the blood-brain barrier, and immune cell entry into the central nervous system.

IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases.

Insulin-like growth factor 2 (IGF2) emerged as a critical mechanism of synaptic plasticity and learning and memory. Deficits in IGF2 in the brain, serum, or cerebrospinal fluid (CSF) are associated with brain diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Increasing IGF2 levels enhances memory in healthy animals and reverses numerous symptoms in laboratory models of aging, neurodevelopmental disorders, and neurodegenerative diseases.

Excessive Protein Accumulation and Impaired Autophagy in the Hippocampus of Angelman Syndrome Modeled in Mice.

Background: Angelman syndrome (AS), a neurodevelopmental disorder caused by abnormalities of the 15q11.2-q13.1 chromosome region, is characterized by impairment of cognitive and motor functions, sleep problems, and seizures.

Hippocampal parvalbumin interneurons play a critical role in memory development.

Episodic memories formed in early childhood rapidly decay, but their latent traces remain stored long term. These memories require the dorsal hippocampus (dHPC) and seem to undergo a developmental critical period. It remains to be determined whether the maturation of parvalbumin interneurons (PVIs), a major mechanism of critical periods, contributes to memory development.

Differential role of neuronal glucose and PFKFB3 in memory formation during development.

The consumption of glucose in the brain peaks during late childhood; yet, whether and how glucose metabolism is differentially regulated in the brain during childhood compared to adulthood remains to be understood. In particular, it remains to be determined how glucose metabolism is involved in behavioral activations such as learning. Here we show that, compared to adult, the juvenile rat hippocampus has significantly higher mRNA levels of several glucose metabolism enzymes belonging to all glucose metabolism pathways, as well as higher levels of the monocarboxylate transporters MCT1 and MCT4 and the glucose transporters endothelial-GLUT1 and GLUT3 proteins.

Computational analysis of memory consolidation following inhibitory avoidance (IA) training in adult and infant rats: Critical roles of CaMKIIα and MeCP2.

Key features of long-term memory (LTM), such as its stability and persistence, are acquired during processes collectively referred to as consolidation. The dynamics of biological changes during consolidation are complex. In adult rodents, consolidation exhibits distinct periods during which the engram is more or less resistant to disruption.

Metabolomic profiling reveals a differential role for hippocampal glutathione reductase in infantile memory formation.

The metabolic mechanisms underlying the formation of early-life episodic memories remain poorly characterized. Here, we assessed the metabolomic profile of the rat hippocampus at different developmental ages both at baseline and following episodic learning. We report that the hippocampal metabolome significantly changes over developmental ages and that learning regulates differential arrays of metabolites according to age.

Recovery of memory from infantile amnesia is developmentally constrained.

Episodic memories formed during infancy are rapidly forgotten, a phenomenon associated with infantile amnesia, the inability of adults to recall early-life memories. In both rats and mice, infantile memories, although not expressed, are actually stored long term in a latent form. These latent memories can be reinstated later in life by certain behavioral reminders or by artificial reactivations of neuronal ensembles activated at training.

Distinct Transcriptomic Profiles in the Dorsal Hippocampus and Prelimbic Cortex Are Transiently Regulated following Episodic Learning.

A fundamental, evolutionarily conserved biological mechanism required for long-term memory formation is rapid induction of gene transcription upon learning in relevant brain areas. For episodic types of memories, two regions undergoing this transcription are the dorsal hippocampus (dHC) and prelimbic (PL) cortex. Whether and to what extent these regions regulate similar or distinct transcriptomic profiles upon learning remain to be understood.

The Ontogeny of Hippocampus-Dependent Memories.

The formation of memories that contain information about the specific time and place of acquisition, which are commonly referred to as "autobiographical" or "episodic" memories, critically relies on the hippocampus and on a series of interconnected structures located in the medial temporal lobe of the mammalian brain. The observation that adults retain very few of these memories from the first years of their life has fueled a long-standing debate on whether infants can make the types of memories that in adults are processed by the hippocampus-dependent memory system, and whether the hippocampus is involved in learning and memory processes early in life. Recent evidence shows that, even at a time when its circuitry is not yet mature, the infant hippocampus is able to produce long-lasting memories.

CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice.

Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments.

Autophagy coupled to translation is required for long-term memory.

An increase in protein synthesis following learning is a fundamental and evolutionarily conserved mechanism of long-term memory. To maintain homeostasis, this protein synthesis must be counterbalanced by mechanisms such as protein degradation. Recent studies reported that macroautophagy/autophagy, a major protein degradation mechanism, is required for long-term memory formation.

A role for CIM6P/IGF2 receptor in memory consolidation and enhancement.

Cation-independent mannose-6-phosphate receptor, also called insulin-like growth factor two receptor (CIM6P/IGF2R), plays important roles in growth and development, but is also extensively expressed in the mature nervous system, particularly in the hippocampus, where its functions are largely unknown. One of its major ligands, IGF2, is critical for long-term memory formation and strengthening. Using CIM6P/IGF2R inhibition in rats and neuron-specific knockdown in mice, here we show that hippocampal CIM6P/IGF2R is necessary for hippocampus-dependent memory consolidation, but dispensable for learning, memory retrieval, and reconsolidation.

Early life experiences selectively mature learning and memory abilities.

The mechanisms underlying the maturation of learning and memory abilities are poorly understood. Here we show that episodic learning produces unique biological changes in the hippocampus of infant rats and mice compared to juveniles and adults. These changes include persistent neuronal activation, BDNF-dependent increase in the excitatory synapse markers synaptophysin and PSD-95, and significant maturation of AMPA receptor synaptic responses.

Enhancing Executive Functions Through Social Interactions: Causal Evidence Using a Cross-Species Model.

It has long been theorized that humans develop higher mental functions, such as executive functions (EFs), within the context of interpersonal interactions and social relationships. Various components of social interactions, such as interpersonal communication, perspective taking, and conforming/adhering to social rules, may create important (and perhaps even necessary) opportunities for the acquisition and continued practice of EF skills. Furthermore, positive and stable relationships facilitate the development and maintenance of EFs across the lifespan.

Corticosterone administration targeting a hypo-reactive HPA axis rescues a socially-avoidant phenotype in scarcity-adversity reared rats.

It is well-established that children from low-income, under-resourced families are at increased risk of altered social development. However, the biological mechanisms by which poverty-related adversities can "get under the skin" to influence social behavior are poorly understood and cannot be easily ascertained using human research alone. This study utilized a rodent model of "scarcity-adversity," which encompasses material resource deprivation (scarcity) and reduced caregiving quality (adversity), to explore how early-life scarcity-adversity causally influences social behavior via disruption of developing stress physiology.

Developmental changes in plasticity, synaptic, glia, and connectivity protein levels in rat basolateral amygdala.

The basolateral complex of amygdala (BLA) processes emotionally arousing aversive and rewarding experiences. The BLA is critical for acquisition and storage of threat-based memories and the modulation of the consolidation of arousing explicit memories, that is, the memories that are encoded and stored by the medial temporal lobe. In addition, in conjunction with the medial prefrontal cortex (mPFC), the BLA plays an important role in fear memory extinction.

Wilm's tumor 1 promotes memory flexibility.

Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however, the underlying mechanisms that enable memory flexibility are still poorly understood. Here, we identify transcriptional repressor Wilm's Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility.

Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons.

Glycogenolysis and lactate transport from astrocytes to neurons is required for long-term memory formation, but the role of this lactate is poorly understood. Here we show that the Krebs cycle substrates pyruvate and ketone body B3HB can functionally replace lactate in rescuing memory impairment caused by inhibition of glycogenolysis or expression knockdown of glia monocarboxylate transporters (MCTs) 1 and 4 in the dorsal hippocampus of rats. In contrast, either metabolite is unable to rescue memory impairment produced by expression knockdown of MCT2, which is selectively expressed by neurons, indicating that a critical role of astrocytic lactate is to provide energy for neuronal responses required for long-term memory.