The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome.

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model, the Ts65Dn, through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem brain tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of DG in the memory deficits observed in Down syndrome.

Prolactin enhances hippocampal synaptic plasticity in female mice of reproductive age.

Dynamic signaling between the endocrine system (ES) and the nervous system (NS) is essential for brain and body homeostasis. In particular, reciprocal interaction occurs during pregnancy and motherhood that may involve changes in some brain plasticity processes. Prolactin (PRL), a hormone with pleiotropic effects on the NS, promotes maternal behavior and has been linked to modifications in brain circuits during motherhood; however, it is unclear whether PRL may regulate synaptic plasticity. Therefore, the main aim of the present work was to determine the cellular and molecular mechanisms triggered by PRL that regulate synaptic plasticity in the hippocampus. By analyzing extracellular recordings in CA3-CA1 synapses of hippocampal slices, we report that PRL modifies short and long-term synaptic plasticity in female mice of reproductive age, but not in sexually immature females or adult males. This effect is carried out through mechanisms that include participation of GABAA receptors and activation of the JAK2-mediated signaling pathway. These findings show for the first time how PRL enhances the synaptic strength in hippocampal circuits and that this effect is sexually dimorphic, which would influence complex brain processes in physiological conditions like pregnancy and lactation.

A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington's disease.

Cognitive dysfunction is an early clinical hallmark of Huntington's disease (HD) preceding the appearance of motor symptoms by several years. Neuronal dysfunction and altered corticostriatal connectivity have been postulated to be fundamental to explain these early disturbances. However, no treatments to attenuate cognitive changes have been successful: the reason may rely on the idea that the temporal sequence of pathological changes is as critical as the changes per se when new therapies are in development. To this aim, it becomes critical to use HD mouse models in which cognitive impairments appear prior to motor symptoms. In this study, we demonstrate procedural memory and motor learning deficits in two different HD mice and at ages preceding motor disturbances. These impairments are associated with altered corticostriatal long-term potentiation (LTP) and specific reduction of dendritic spine density and postsynaptic density (PSD)-95 and spinophilin-positive clusters in the cortex of HD mice. As a potential mechanism, we described an early decrease of Kalirin-7 (Kal7), a guanine-nucleotide exchange factor for Rho-like small GTPases critical to maintain excitatory synapse, in the cortex of HD mice. Supporting a role for Kal7 in HD synaptic deficits, exogenous expression of Kal7 restores the reduction of excitatory synapses in HD cortical cultures. Altogether, our results suggest that cortical dysfunction precedes striatal disturbances in HD and underlie early corticostriatal LTP and cognitive defects. Moreover, we identified diminished Kal7 as a key contributor to HD cortical alterations, placing Kal7 as a molecular target for future therapies aimed to restore corticostriatal function in HD.

Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling.

Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor-independent form of LTP (CAF LTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB-mediated signaling required for the expression of CAF LTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAF LTP, a process that requires cytosolic free Ca2+ . Consistent with the involvement of IRS2 signals in caffeine-mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2-/- mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3-kinase (PI3K) pathway. These findings indicate that TrkB-IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

Defective engram allocation contributes to impaired fear memory performance in Down syndrome.

Down syndrome (DS) is the most common genetic form of intellectual disability (ID). The cellular and molecular mechanisms contributing to ID in DS are not completely understood. Recent evidence indicates that a given memory is encoded by sparsely distributed neurons, highly activated during learning, the engram cells. Intriguingly, mechanisms that are of paramount importance for engram formation are impaired in DS. Here we explored engram formation in a DS mouse model, the Ts65Dn and we found a reduced number of engram cells in the dentate gyrus (DG), suggesting reduced neuronal allocation to engrams. We also show that trisomic engram cells present reduced number of mature spines than WT engram cells and their excitability is not enhanced during memory recall. In fact, activation of engram cells using a chemogenetic approach does not recover memory deficits in Ts65Dn. Altogether, our findings suggest that perturbations in engram neurons may play a significant role in memory alterations in DS.

The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity and memory deficits in Down syndrome.

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of the DG in the memory deficits observed in Down syndrome.

Neurodevelopmental disorders: 2021 update.

One of the current challenges in the field of neurodevelopmental disorders (NDDs) is still to determine their underlying aetiology and risk factors. NDDs comprise a diverse group of disorders primarily related to neurodevelopmental dysfunction including autism spectrum disorder (ASD), developmental delay, intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD) that may present with a certain degree of cognitive dysfunction and high prevalence of neuropsychiatric outcomes. Last year, advances in human genomics have begun to shed light on the genetic architecture of these disorders and large-scale sequencing studies are starting to reveal mechanisms that range from unique genomic DNA methylation patterns (i.e. "episignatures") to highly polygenic conditions. In addition, the contribution of de novo somatic mutations to neurodevelopmental diseases is being recognized. However, progressing from genetic findings to underlying neuropathological mechanisms has proved challenging, due to the increased resolution of the molecular and genetic assays. Advancement in modelling tools is likely to improve our understanding of the origin of neurodevelopmental disorders and provide insight into their developmental mechanisms. Also, combined in vivo editing of multiple genes and single-cell RNA-sequencing (scRNA-seq) are bringing us into a new era of understanding the molecular neuropathology of NDDs.

Increase in serum prolactin levels in females improves the performance of spatial learning by promoting changes in the circuital dynamics of the hippocampus.

Beyond the direct physiological functions associated with motherhood in mammals, previous studies have suggested the potential role of prolactin (Prl) in distinct brain processes such as neuroprotection, neurogenesis, and stress responses. However, the cognitive influence of Prl remains unclear, particularly regarding the mechanisms of acquisition, consolidation and retrieval of information in the brain. Using chronic implanted electrodes in freely moving female mice combined with behavioral tests, we investigated the rhythmic activity changes induced by Prl in a model of hippocampus-dependent learning and memory. Our results show that Prl improves the learning of a spatial memory task in the acquisition stage. The main variations at the circuitry level were in the theta frequency band (4-8 Hz and 8-12 Hz), marked by a faster change in oscillatory activity with no modifications to higher frequencies. These results show that Prl plays a significant role in the acquisition of information during learning of a spatial memory task, suggesting that an increase in Prl levels may induce changes in circuital network plasticity.

Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation.

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.

Calcium extrusion mechanisms in dendrites of mouse hippocampal CA1 inhibitory interneurons.

Local circuit GABAergic inhibitory interneurons control the integration and transfer of information in many brain regions. Several different forms of plasticity reported at interneuron excitatory synapses are triggered by cell- and synapse-specific postsynaptic calcium (Ca2+) mechanisms. To support this function, the spatiotemporal dynamics of dendritic Ca2+ elevations must be tightly regulated. While the dynamics of postsynaptic Ca2+ signaling through activation of different Ca2+ sources has been explored, the Ca2+ extrusion mechanisms that operate in interneuron dendrites during different patterns of activity remain largely unknown. Using a combination of whole-cell patch-clamp recordings and two-photon Ca2+ imaging in acute mouse hippocampal slices, we characterized the Ca2+ extrusion mechanisms activated by Ca2+ transients (CaTs) associated with backpropagating action potentials (bAPs) in dendrites of hippocampal CA1 stratum radiatum interneurons. Our data showed that Ca2+ clearance increased as a function of activity, pointing to an activity-dependent recruitment of specific Ca2+ extrusion mechanisms. bAP-CaTs were significantly prolonged in the presence of the plasma membrane Ca2+ ATPase (PMCA) and Na+/Ca2+ exchanger (NCX) inhibitors as well as the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) and the mitochondria Ca2+ uniporter (MCU) blockers. While PMCA, NCX and SERCA pumps cooperated in the cytosolic Ca2+ removal at a wide range of concentrations, the MCU was only activated at higher Ca2+ loads produced by repetitive interneuron firing. These results identify a division of labor between distinct Ca2+ extrusion mechanisms shaping dendritic Ca2+ dynamics and possibly contributing to activity-dependent regulation of synaptic inputs in interneurons. In addition, the MCU activated by larger Ca2+ levels may be involved in the activity-dependent ATP production or interneuron-selective vulnerability associated with cytosolic Ca2+ overloads under pathological conditions.

Prostaglandin E2 EP1 receptor antagonist improves motor deficits and rescues memory decline in R6/1 mouse model of Huntington's disease.

In this study, we evaluated the potential beneficial effects of antagonizing prostaglandin E2 (PGE2) EP1 receptor on motor and memory deficits in Huntington's disease (HD). To this aim, we implanted an osmotic mini-pump system to chronically administrate an EP1 receptor antagonist (SC-51089) in the R6/1 mouse model of HD, from 13 to 18 weeks of age, and used different paradigms to assess motor and memory function. SC-51089 administration ameliorated motor coordination and balance dysfunction in R6/1 mice as analyzed by rotarod, balance beam, and vertical pole tasks. Long-term memory deficit was also rescued after EP1 receptor antagonism as assessed by the T-maze spontaneous alternation and the novel object recognition tests. Additionally, treatment with SC-51089 improved the expression of specific synaptic markers and reduced the number of huntingtin nuclear inclusions in the striatum and hippocampus of 18-week-old R6/1 mice. Moreover, electrophysiological studies showed that hippocampal long-term potentiation was significantly recovered in R6/1 mice after EP1 receptor antagonism. Altogether, these results show that the antagonism of PGE2 EP1 receptor has a strong therapeutic effect on R6/1 mice and point out a new therapeutic candidate to treat motor and memory deficits in HD.

Neurotrophin receptor p75(NTR) mediates Huntington's disease-associated synaptic and memory dysfunction.

Learning and memory deficits are early clinical manifestations of Huntington's disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75(NTR) negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75(NTR) function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75(NTR) are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75(NTR) levels in HD mutant mice heterozygous for p75(NTR) prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75(NTR) in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75(NTR) in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75(NTR) mediates synaptic, learning, and memory dysfunction in HD.