Behavioral deficits and subregion-specific suppression of LTP in mice expressing a population of mutant NMDA receptors throughout the hippocampus

The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1^N598R allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.According to Hebb''s postulate, neurons require a molecular mechanism to detect synchronous activity in order to change the strength of synaptic connectivity (Hebb 1949). NMDA receptors (NMDARs) are molecular coincidence detectors, and selective NMDAR antagonists block the induction of long-term potentiation (LTP) in both the dentate gyrus (DG) and CA1 regions of the hippocampus (Bliss and Collingridge 1993; Martin et al. 2000). NMDARs have been long known for their role in spatial learning, but more recently have been implicated in other forms of cognitive function and dysfunction (Gruart et al. 2006; Whitlock et al. 2006; Castner and Williams 2007; Kristiansen et al. 2007; Wilson and Linster 2008).Neuronal NMDARs are hetero-tetrameric ligand-gated ion channels typically comprised of two types of subunits. Two copies of the mandatory GluN1 subunit (or NR1 subunit [Collingridge et al. 2009] encoded by Grin1) are associated with two copies from the GluN2 family, GluN2A–D (or NR2A–D). The GluN1 subunit is expressed ubiquitously both spatially and temporally throughout the developing and adult brain. Global knockout mice models of the GluN1 subunit are postnatally lethal within hours after birth (Forrest et al. 1994; Li et al. 1994), and cell-specific GluN1 mice knockouts (Tsien et al. 1996; Nakazawa et al. 2002; McHugh et al. 2007; Niewoehner et al. 2007) have provided insights on how specific synapses and regional neuronal networks are dependent on NMDAR function.The early postnatal lethality of the global GluN1 knockout is in contrast to the null mutants of the four AMPA receptor genes and other major synaptic proteins, such as αCaMKII (Silva et al. 1992a,b; Jia et al. 1996; Zamanillo et al. 1999; Meng et al. 2003). This can be at least partially explained by the absence of any close GluN1 homologs, which could functionally compensate for the absence of the GluN1 subunit. Recombinant expression studies defined the GluN1 subunit as a mandatory component of NMDARs. This constellation provides a specific opportunity to test whether different local neuronal subnetworks are affected differentially by mutant Grin1 alleles associated with subtle alterations of the functional properties of NMDARs.GluN1 subunits with the N598R point mutation (GluN1^R) yield functional NMDARs that are Mg²⁺ insensitive and Ca²⁺ impermeable (Burnashev et al. 1992; Mori et al. 1992). The Grin1^N598R allele that codes for GluN1^R subunits is a gain-of-function mutation that is dominant lethal, even in heterozygous and hemizygous lines (Single et al. 2000; Rudhard et al. 2003). NMDARs with GluN1^R subunits do not act as coincidence detectors and, interestingly, mice expressing exclusively the GluN1^R allele lack whisker-related pattern formation in the neonate brainstem (Rudhard et al. 2003).To investigate the functional importance of GluN1 subunits with the N598R point mutation, we took advantage of the generation of a variant mutant line of mice (GluN1^Rneo/+) expressing a minority (around 10%) of these mutant NMDARs. Even though the majority of the NMDARs are normal, all neurons expressing NMDARs will contain a subset of receptors carrying this mutation.Therefore, this mouse model is an ideal candidate to study the impact of subtle alterations of NMDAR function on different neuronal networks, such as those comprising the hippocampal formation.Studies examining region-specific targeted disruption of GluN1 expression in subregions of the hippocampus have revealed subtle yet important contributions of this NMDAR subunit in synaptic plasticity and spatial learning and memory. CA1-restricted knockout of GluN1 expression in the hippocampus caused impaired spatial learning and memory as well as reduced CA1-LTP (Tsien et al. 1996). In the case of the disruption of GluN1 expression in the DG region of the hippocampus, more subtle behavioral impairments were apparent, including the inability to discriminate between two similar contexts (pattern separation) and deficits in spatial working memory despite normal LTP in the CA1 region (McHugh et al. 2007; Niewoehner et al. 2007).Our GluN1^Rneo/+ mice differ from the region-specific GluN1 mutant mice in that they express the mutant hypomorph at the same level in different subregions of the hippocampus. Interestingly, we found that this allele leads to substantial differences in short- and long-term plasticity between area CA1 and the DG of the hippocampus. The specific impairment in the DG was accompanied by impaired spatial recognition, spatial learning, reversal learning, and retention. Our data establish the possibility of a circuit-specific phenotype caused by a mutant variant of a globally expressed major nonredundant synaptic protein.     

Discriminant validity of the Conners’ scales for ADHD subtypes

Differential diagnosis and treatment of children with Attention-Deficit/Hyperactivity Disorder (ADHD) remains difficult and controversial, particularly when children present with concomitant academic and behavior problems. Describing a sample of 184 chil-dren referred for evaluation in a university-affiliated outpatient pediatric clinic, this study subsequently examined the discriminant validity of the Conners’ parent and teacher rating scales for ADHD subtypes with and without comorbid conditions. Although discriminant analyses suggest several Conners’ subscales help differentiate subtypes, multimethod evaluations using a variety of data sources are necessary for accurate identification and classification of the disorder with and without comorbid conditions. These data were previously reported at the 107^th Annual Convention of the American Psychological Association, Boston, Massachusetts. The authors express gratitude to Ross D. Crosby, Ph.D., Director of Biomedical Statistics and Methodology at the Neuropsychiatrie Research Institute, for his pre-submission review of the article.     

The Scarlet Letter Study: Five Days of Social Ostracism

Abstract

Over the course of 5 consecutive days, each author agreed to be ostracized for a day at work by the other four coauthors. All coauthors’ offices were in close proximity and were located solely on a single floor and wing of their academic building. Each morning, the name of that day's ostracized individual was drawn, and a scarlet letter “O” was placed above that individual's office door. Ostracizers were instructed to ignore the “Os” by not looking at them, speaking to them, or responding to anything they said. Open-ended individual event-contingent diaries were kept to record participants’ thoughts, feelings, and behaviors each time they were reminded of the ostracism. Despite foreknowledge and consent, attributional confusion surfaced and strong aversive reactions were reported. Findings are framed in terms of Williams's (1997) model of ostracism     

Child Delinquents: Examining the Market for Criminal Futures

This article investigates child delinquency (offenders younger than 13 years of age). The population of child delinquents under various dispositions in the state of Louisiana, at one point in time, is described. Eighty youth are examined using the following characteristics: Race, Gender, Age, Offense Type (violent, nonviolent) Crime Category (felony, status offense, misdemeanor, and felony or misdemeanor) and Disposition (supervision, secure custody, and non-secure custody). Child delinquency is an important topic because the younger the age of first offense the greater the probability of a delinquent and criminal career. Findings reveal very few youth in secure custody and black males account for over half of the population of child delinquents. Over 75% of the population was 12 years of age.     

Effort denial in self-deception

We propose a mixed belief model of self-deception. According to the theory, people distribute belief over two possible causal paths to an action, one where the action is freely chosen and one where it is due to factors outside of conscious control. Self-deceivers take advantage of uncertainty about the influence of each path on their behavior, and shift weight between them in a self-serving way. This allows them to change their behavior to provide positive evidence and deny doing so, enabling diagnostic inference to a desired trait. In Experiment 1, women changed their pain tolerance to provide positive evidence about the future quality of their skin, but judgments of effort claimed the opposite. This “effort denial” suggests that participants’ mental representation of their behavior was dissociated from their actual behavior, facilitating self-deception. Experiment 2 replicated the pattern in a hidden picture task where search performance was purportedly linked to self-control.     

Complexities of Genetic Counseling for ALS: A Case of Two Siblings with Discordant Genetic Test Results

Rapid advances in the genetics of amyotrophic lateral sclerosis (ALS) have dramatically changed the approach of clinicians and researchers to the motor neuron diseases. We report two siblings in whom the genetic study provided conflicting results, hence raising a number of issues which deserve to be considered by clinicians involved in genetic testing for ALS. The first patient died within 2 years of ALS onset, while her brother still manages to walk unaided, 7 years into onset. Genetic analyses, performed on the first patient as part of a research protocol, and as clinical genetic testing on the brother, provided different results. Results for Patient 1 were negative for all investigated genes, thus suggesting that her disease may be a phenocopy, while her brother carried an autosomal dominant TARDBP mutation (p.A382T). A multidisciplinary approach may help patients and clinicians face the emerging dilemmas in such a complex field. Sharing and updating of advances, not to mention uncertainties inherent to current knowledge, with patients and families may prove to be an effective way to support them and to make them aware of the present limits of our knowledge and of the blurred border between research and clinical practice.