Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1.

NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory.

The impact of in hospital patient-education intervention on older people's attitudes and intention to have their benzodiazepines deprescribed: a feasibility study.

BACKGROUND: Long-term benzodiazepine use in the older population is common and is associated with significant harm. The provision of a patient-educational booklet during hospitalization may encourage patients to discuss review and possible deprescribing of benzodiazepine therapy with their health professionals. The aim of this study was to assess the feasibility and effect of a patient empowerment intervention in hospital inpatients on patient initiation of a discussion about deprescribing benzodiazepines versus usual care. METHODS: A feasibility interventional study using a patient-empowerment education intervention was conducted at a Sydney teaching hospital. Patients aged ⩾ 65 years, prescribed a benzodiazepine, and able to provide consent were invited to participate in the study. Participants were randomly allocated to intervention or control group (1:1). Intervention participants received the patient-empowerment booklet and control received usual care. All participants received 1-month follow-up phone interviews to assess medication and attitudinal changes. RESULTS: A total of 42 participants were recruited (20 intervention and 22 control). The average age was 71.5 (interquartile range: 69.0-80.3) and 54.8% were females. There was no difference in baseline characteristics between intervention and control groups (p > 0.05). At baseline, 65.0% of participants (53.0% intervention, 86.0% control) were not concerned about the potential benzodiazepine side effects. Twenty-nine participants (15 intervention and 14 control) completed 1-month follow up; 22 participants (11 intervention and 11 control) were discharged on the benzodiazepine. Among these, 13 (59.1%) had ceased benzodiazepine at 1-month follow up [46.2% (n = 6) intervention; 53.8% (n = 7) control]. In the intervention group, 33.3% (n = 5) of participants had initiated a discussion with their doctor or pharmacist about stopping the benzodiazepine compared with 35.7% (n = 5) in the control group. CONCLUSION: Cessation of benzodiazepines 1 month following discharge was common. Future larger studies are required to confirm the effectiveness of providing a patient-empowerment booklet on reducing benzodiazepine use and other potentially inappropriate medications.

Activation of Entorhinal Cortical Projections to the Dentate Gyrus Underlies Social Memory Retrieval.

Social interactions are essential to our mental health, and a deficit in social interactions is a hallmark characteristic of numerous brain disorders. Various subregions within the medial temporal lobe have been implicated in social memory, but the underlying mechanisms that tune these neural circuits remain unclear. Here, we demonstrate that optical activation of excitatory entorhinal cortical perforant projections to the dentate gyrus (EC-DG) is necessary and sufficient for social memory retrieval. We further show that inducible disruption of p21-activated kinase (PAK) signaling, a key pathway important for cytoskeletal reorganization, in the EC-DG circuit leads to impairments in synaptic function and social recognition memory, and, importantly, optogenetic activation of the EC-DG terminals reverses the social memory deficits in the transgenic mice. These results provide compelling evidence that activation of the EC-DG pathway underlies social recognition memory recall and that PAK signaling may play a critical role in modulating this process.

Publisher Correction: The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning.

In the version of this article initially published, the wrong version of Supplementary Fig. 10 was posted and the city for affiliation 4, the Co-innovation Center of Neuroregeneration, Nantong University, was given as Nanjing instead of Nantong. The errors have been corrected in the HTML and PDF versions of the article.

Three-chamber Social Approach Task with Optogenetic Stimulation (Mice).

The formation of social relationships via social interactions and memory are essential for one's physical and mental health. To date, rodent studies have used the three-chamber social approach test to measure social approach, social novelty, and social memory. In recent years, techniques including optogenetics have been developed to acutely control the activity of genetically defined populations of neurons. Recent studies have even combined optogenetics with advanced temporal gene expression control systems to label certain populations of neurons during learning and subsequently reactivated for memory testing. We combined optogenetic targeting with the three-chamber social approach test to examine particular neural circuits of interest during social memory encoding or retrieval. First, we stereotaxically infected specific brain areas with viral-encoding opsins that acutely activate or inhibit the firing of the neurons. Next, we subjected the mice to the three-chamber behavioral paradigm while delivering light during social memory encoding or retrieval. Lastly, the mice were tested with the delivery of light in a counter-balanced manner which allows each subject to be its own internal control. Thus, the optogenetic stimulation coupled with the three-chamber social approach test is a well-validated paradigm to explore the contribution of diverse brain circuits in various social cognition processes.

The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning.

Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.

Developmental regulation of hippocampal long-term depression by cofilin-mediated actin reorganization.

Long lasting synaptic plasticity involves both functional and morphological changes, but how these processes are molecularly linked to achieve coordinated plasticity remains poorly understood. Cofilin is a common target of multiple signaling pathways at the synapse and is required for both functional and spine plasticity, but how it is regulated is unclear. In this study, we investigate whether the involvement of cofilin in plasticity is developmentally regulated by examining the role of cofilin in hippocampal long-term depression (LTD) in both young (2 weeks) and mature (2 months) mice. We show that both total protein level of cofilin and its activation undergo significant changes as the brain matures, so that although the amount of cofilin decreases significantly in mature mice, its regulation by protein phosphorylation becomes increasingly important. Consistent with these biochemical data, we show that cofilin-mediated actin reorganization is essential for LTD in mature, but not in young mice. In contrast to cofilin, the GluA2 interactions with NSF and PICK1 appear to be required in both young and mature mice, indicating that AMPAR internalization is a common key mechanism for LTD expression regardless of the developmental stages. These results establish the temporal specificity of cofilin in LTD regulation and suggest that cofilin-mediated actin reorganization may serve as a key mechanism underlying developmental regulation of synaptic and spine plasticity. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus.

PAK1 inhibitors are known to markedly improve social and cognitive function in several animal models of brain disorders, including autism, but the underlying mechanisms remain elusive. We show here that disruption of PAK1 in mice suppresses inhibitory neurotransmission through an increase in tonic, but not phasic, secretion of endocannabinoids (eCB). Consistently, we found elevated levels of anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) following PAK1 disruption. This increased tonic AEA signaling is mediated by reduced cyclooxygenase-2 (COX-2), and COX-2 inhibitors recapitulate the effect of PAK1 deletion on GABAergic transmission in a CB1 receptor-dependent manner. These results establish a novel signaling process whereby PAK1 upregulates COX-2, reduces AEA and restricts tonic eCB-mediated processes. Because PAK1 and eCB are both critically involved in many other organ systems in addition to the brain, our findings may provide a unified mechanism by which PAK1 regulates these systems and their dysfunctions including cancers, inflammations and allergies.

Mouse Genetic Models of Human Brain Disorders.

Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases.

Neuroligin 1 regulates spines and synaptic plasticity via LIMK1/cofilin-mediated actin reorganization.

Neuroligin (NLG) 1 is important for synapse development and function, but the underlying mechanisms remain unclear. It is known that at least some aspects of NLG1 function are independent of the presynaptic neurexin, suggesting that the C-terminal domain (CTD) of NLG1 may be sufficient for synaptic regulation. In addition, NLG1 is subjected to activity-dependent proteolytic cleavage, generating a cytosolic CTD fragment, but the significance of this process remains unknown. In this study, we show that the CTD of NLG1 is sufficient to (a) enhance spine and synapse number, (b) modulate synaptic plasticity, and (c) exert these effects via its interaction with spine-associated Rap guanosine triphosphatase-activating protein and subsequent activation of LIM-domain protein kinase 1/cofilin-mediated actin reorganization. Our results provide a novel postsynaptic mechanism by which NLG1 regulates synapse development and function.

PAK1 regulates cortical development via promoting neuronal migration and progenitor cell proliferation.

BACKGROUND: p21-activated kinase 1 (PAK1) is a serine/threonine kinase known to be activated by the Rho family small GTPases and to play a key role in cytoskeletal reorganization, spine morphology and synaptic plasticity. PAK1 is also implicated in a number of neurodevelopmental and neurodegenerative diseases, including autism, intellectual disability and Alzheimer's disease. However, the role of PAK1 in early brain development remains unknown. RESULTS: In this study, we employed genetic manipulations to investigate the role of PAK1 in the cerebral cortical development in mice. We showed that compared to the wild type littermates, PAK1 knockout mice have a reduction in the number of pyramidal neurons in several layers of the cerebral cortex, which is associated with a smaller pool of neural progenitor cells and impaired neuronal migration. CONCLUSION: These results suggest that PAK1 regulates cortical development by promoting the proliferation of neural progenitor cells and facilitating the migration of these neurons to specific regions of the cortex.