APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-ß precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.

Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France.

BACKGROUND: Apathy and depression are two early behavioral symptoms in Alzheimer's disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. OBJECTIVE: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. METHODS: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. RESULTS: Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. CONCLUSION: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely-compared to depression-to be associated with conversion to dementia.

Strategy inference during learning via cognitive activity-based credit assignment models.

We develop a method for selecting meaningful learning strategies based solely on the behavioral data of a single individual in a learning experiment. We use simple Activity-Credit Assignment algorithms to model the different strategies and couple them with a novel hold-out statistical selection method. Application on rat behavioral data in a continuous T-maze task reveals a particular learning strategy that consists in chunking the paths used by the animal. Neuronal data collected in the dorsomedial striatum confirm this strategy.

Episodic Memory formation: A review of complex Hippocampus input pathways.

Memories of everyday experiences involve the encoding of a rich and dynamic representation of present objects and their contextual features. Traditionally, the resulting mnemonic trace is referred to as Episodic Memory, i.e. the "what", "where" and "when" of a lived episode. The journey for such memory trace encoding begins with the perceptual data of an experienced episode handled in sensory brain regions. The information is then streamed to cortical areas located in the ventral Medio Temporal Lobe, which produces multi-modal representations concerning either the objects (in the Perirhinal cortex) or the spatial and contextual features (in the parahippocampal region) of the episode. Then, this high-level data is gated through the Entorhinal Cortex and forwarded to the Hippocampal Formation, where all the pieces get bound together. Eventually, the resulting encoded neural pattern is relayed back to the Neocortex for a stable consolidation. This review will detail these different stages and provide a systematic overview of the major cortical streams toward the Hippocampus relevant for Episodic Memory encoding.

The Amyloid Precursor Protein C-Terminal Domain Alters CA1 Neuron Firing, Modifying Hippocampus Oscillations and Impairing Spatial Memory Encoding.

There is a growing consensus that Alzheimer's disease (AD) involves failure of the homeostatic machinery, which underlies the firing stability of neural circuits. What are the culprits leading to neuron firing instability? The amyloid precursor protein (APP) is central to AD pathogenesis, and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothesize that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological, and behavioral techniques, we show that pathological AICD levels weaken CA1 neuron firing activity through a gene-transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the γ-frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal aging to AD.

A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies.

SCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS. We used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling. Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.

Developmental Requirement of Homeoprotein Otx2 for Specific Habenulo-Interpeduncular Subcircuits.

The habenulo-interpeduncular system (HIPS) is now recognized as a critical circuit modulating aversion, reward, and social behavior. There is evidence that dysfunction of this circuit leads to psychiatric disorders. Because psychiatric diseases may originate in developmental abnormalities, it is crucial to investigate the developmental mechanisms controlling the formation of the HIPS. Thus far, this issue has been the focus of limited studies. Here, we explored the developmental processes underlying the formation of the medial habenula (MHb) and its unique output, the interpeduncular nucleus (IPN), in mice independently of their gender. We report that the Otx2 homeobox gene is essential for the proper development of both structures. We show that MHb and IPN neurons require Otx2 at different developmental stages and, in both cases, Otx2 deletion leads to disruption of HIPS subcircuits. Finally, we show that Otx2+ neurons tend to be preferentially interconnected. This study reveals that synaptically connected components of the HIPS, despite radically different developmental strategies, share high sensitivity to Otx2 expression.SIGNIFICANCE STATEMENT Brain reward circuits are highly complex and still poorly understood. In particular, it is important to understand how these circuits form as many psychiatric diseases may arise from their abnormal development. This work shows that Otx2, a critical evolutionary conserved gene implicated in brain development and a predisposing factor for psychiatric diseases, is required for the formation of the habenulo-interpeduncular system (HIPS), an important component of the reward circuit. Otx2 deletion affects multiple processes such as proliferation and migration of HIPS neurons. Furthermore, neurons expressing Otx2 are preferentially interconnected. Therefore, Otx2 expression may represent a code that specifies the connectivity of functional subunits of the HIPS. Importantly, the Otx2 conditional knock-out animals used in this study might represent a new genetic model of psychiatric diseases.

Identification of an acute functional cross-talk between amyloid-ß and glucocorticoid receptors at hippocampal excitatory synapses.

Amyloid-ß is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-ß (Aßο) is now believed to represent the main Amyloid-ß species affecting synapse function. Yet, the exact molecular mechanism by which Aßο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aßο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aß and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aßo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aßo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aßo-mediated LTP impairment, but not Aßo-mediated LTD induction. The necessity of neuronal GRs for Aßo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aß activities at excitatory synapses.

Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein.

The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer's disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in vivo AICD expression, ex vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GluN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GluN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure.

Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease.

The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.

Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates.

Three experiments investigated the role in memory processing of dopamine (DA) afferents to the hippocampus (HPC) that arise from the ventral tegmental area. One hypothesis is that D(1)/D(5) receptor activation in HPC is necessary for the encoding of novel, episodic-like information; the other is that DA activation ensures the greater temporal persistence of transient hippocampal memory traces. Rats (n = 35) were trained, in separate experiments using an episodic-like memory task, to learn six paired associates (PAs) in an "event arena" involving a repeated association between specific flavors of food and locations in space. After 6 weeks of training, rats had learned a "schema" such that two new paired associates could be acquired in a single trial in one session (episodic-like memory). We show that encoding of novel PAs is sensitive to intrahippocampal microinfusion of the NMDA antagonist d-AP-5. Experiment 1 established that intrahippocampal infusion of the D(1)/D(5) dopaminergic antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] before encoding of new PAs caused impaired memory 24 h later but that SCH23390 had no effect on the later memory of previously established PAs. Experiment 2 established that SCH23390 modulated the persistence of new memories over time (30 min vs 24 h) rather than affecting initial encoding. Experiment 3 revealed that the impact of SCH23390 was not mediated by state dependence nor had an effect on memory retrieval. These findings support the second hypothesis and establish that persistent, long-term memory of rapid, hippocampal-mediated acquisition of new paired associates requires activation of D(1)/D(5) receptors in HPC at or around the time of encoding.

Schemas and memory consolidation.

Memory encoding occurs rapidly, but the consolidation of memory in the neocortex has long been held to be a more gradual process. We now report, however, that systems consolidation can occur extremely quickly if an associative "schema" into which new information is incorporated has previously been created. In experiments using a hippocampal-dependent paired-associate task for rats, the memory of flavor-place associations became persistent over time as a putative neocortical schema gradually developed. New traces, trained for only one trial, then became assimilated and rapidly hippocampal-independent. Schemas also played a causal role in the creation of lasting associative memory representations during one-trial learning. The concept of neocortical schemas may unite psychological accounts of knowledge structures with neurobiological theories of systems memory consolidation.

Does prenatal stress affect latent inhibition? It depends on the gender.

The present experiment was designed to examine the effects of prenatal stress and gender in latent inhibition. Prenatal stress has been proposed as a risk factor both for depression and for schizophrenia, and both of these syndromes are associated with alterations in the functional state of the dopamine system. There is also some evidence that prenatal stress can produce changes in dopamine activity, although the details of the stress-induced changes are a matter of debate. Latent inhibition (LI), which is strongly dependent on dopaminergic activity, consists in delayed Pavlovian conditioning about a stimulus that previously signalled no consequence. We induced prenatal stress by exposing gestating dams to a daily constraint stress during the last week of pregnancy. We tested the rats for LI of conditioned taste aversion by exposing them to sucrose for 3 days prior to conditioning. Irrespective of stress or gender, latent inhibition was observed but the degree of LI varied as a function of both prenatal stress and gender. Unstressed males showed less LI than unstressed females, but prenatal stress increased the amount of LI only in the males. These results are inconsistent with the use of prenatal stress as an animal model for schizophrenia. A model is proposed that accounts for the relationships between gender, dopamine function, cognitive changes and psychiatric pathology.

Chronic interferon-alpha potentiates latent inhibition in rats.

Several recent reports based on microdialysis have shown that repeated injections of IFN-alpha induce reduced dopamine (DA) activity in the rodent brain, and specifically within the striatum. This mesolimbic DA system is thought to play a central role in controlling latent inhibition (LI), which refers to the phenomenon in which conditioning proceeds more slowly to an irrelevant pre-exposed (PE) stimulus. The purpose of the present experiment was to evaluate whether chronic treatment with IFN-alpha may induce similar effects on LI as other DA-depleting manipulations. Rats were injected daily, for 24 days either with 10(4)IU IFN-alpha or vehicle, while monitoring their locomotor activity in photocell cages. No changes in locomotor activity, either during the acute period after the first injection, or progressively over the chronic period were observed. LI was then evaluated in these rats with a Conditioned Taste Aversion (CTA) paradigm. Half of each group of rats were pre-exposed to the 5% sucrose Conditioned Stimulus (CS) for 30 min on three successive days before the conditioning session in which the 30 min access to the 5% sucrose solution was followed by a 0.15M injection of 127 mg/kg LiCl. Two test sessions, in which rats were given a choice between the 5% sucrose solution and water, were given 48 and 72 h after the conditioning session. The results showed moderate LI in the control group, which was considerably potentiated in the IFN-alpha group despite the absence of any change in locomotor activity. These results are interpreted as providing indirect support for the theory that suggests that LI depends on DA activity in the nucleus accumbens (NAcc).

Antidepressant reversal of interferon-alpha-induced anhedonia.

Interferon-alpha(IFN-alpha) is used clinically in the treatment of several pathologies such as hepatitis C and various cancers. The positive therapeutic potential is however often limited by negative secondary effects which include major depression, one of the cardinal symptoms of which is anhedonia which has been operationalized as a decreased sensitivity to rewards (inability to experience pleasure). Previous studies have demonstrated the existence of anhedonia in rats following an acute injection of IFN-alpha at doses corresponding to those used in clinical applications. If this previously demonstrated anhedonia is indeed part of a depression syndrome in rats, this behavioural symptom should be reversible by the administration of antidepressants. The objective of the present experiment was to determine whether two commonly used antidepressants (desipramine and fluoxetine) were effective in ameliorating IFN-alpha-induced anhedonia in rats. The experiment consisted of two phases. In the first, the effects of daily systemic injections of 104 units/kg of IFN-alpha (or vehicle) were evaluated with the three-bottle (1%, 8%, and 32%) sucrose-consumption test. In the second phase of the experiment, in addition to continued injections of IFN-, different groups received daily injections of desipramine (7.5 mg/kg ip), fluoxetine (7.5 mg/kg ip), or vehicle. The IFN-alpha injections during Phase 1 resulted in clear anhedonia, as expressed by increased consumption of the 32% solution and decreased consumption of 1% over the 33 days of this phase. After 15 days of antidepressant treatments, 32% sucrose consumption returned to baseline values. We have therefore confirmed that IFN-alpha-induced anhedonia is susceptible to reversal following chronic antidepressant treatment and thus it may appear timely to consider the prophylactic use of such in particular patients prescribed IFN in the clinic.