Persistence of humoral response upon SARS-CoV-2 infection.

SARS-CoV-2 continues to leave its toll on global health and the economy. Management of the pandemic will rely heavily on the degree of adaptive immunity persistence following natural SARS-CoV-2 infection. Along with the progression of the pandemic, more literature on the persistence of the SARS-CoV-2-specific antibody response is becoming available. Here, we summarize findings on the persistence of the humoral, including neutralizing antibody, response at three to eight months post SARS-CoV-2 infection in non-pregnant adults. While the comparability of the literature is limited, findings on the detectability of immunoglobulin G class of antibodies (IgG) were most consistent and were reported in most studies to last for six to eight months. Studies investigating the response of immunoglobins M and A (IgM, IgA) were limited and reported mixed results, in particular, for IgM. The majority of studies observed neutralizing antibodies at all time points tested, which in some studies lasted up to eight months. The presence of neutralizing antibodies has been linked to protection from re-infection, suggesting long-term immunity to SARS-CoV-2. These neutralizing capacities may be challenged by emerging virus variants, but mucosal antibodies as well as memory B and T cells may optimize future immune responses. Thus, further longitudinal investigation of PCR-confirmed seropositive individuals using sensitive assays is warranted to elucidate the nature and duration of a more long-term humoral response.

Cannabis use and psychosis: a review of reviews.

We conducted a systematic review of meta-analyses and systematic reviews to evaluate the impact of cannabis use on the onset and course of psychoses. Following a systematic literature search of five data bases (2005-2016) and consecutive structured evaluation, we were able to include 26 systematic reviews and meta-analyses. The methodological quality of the included publications were in the range of high and poor. The scientific literature indicates that psychotic illness arises more frequently in cannabis users compared to non-users, cannabis use is associated with a dose-dependent risk of developing psychotic illness, and cannabis users have an earlier onset of psychotic illness compared to non-users. Cannabis use was also associated with increased relapse rates, more hospitalizations and pronounced positive symptoms in psychotic patients. We make recommendations about the type of research that is required to better characterize the relationship between cannabis use and the development and outcomes of psychosis.

How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.

Correction to: How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

The article "How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review", written by Eva Hoch, was originally published Online First without open access. After publication in volume 269, issue 1, page 87-105 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

[Efficacy and safety of medicinal cannabis: results of the CaPRis study]. / Wirksamkeit und Sicherheit von Cannabisarzneimitteln: Ergebnisse der CaPRis-Studie.

In the 1990s, the endocannabinoid system was discovered as part of the human physiology. Since then, the effects of cannabis as a medicine have been researched more systematically. To summarize the scientific knowledge, the German Federal Ministry of Health commissioned an expertise.The project "Cannabis: Potential and Risks: a Scientific Analysis" (CaPRis), which started in 2016, aimed at analyzing the potential of medicinal cannabis and the risks of recreational cannabis use. A search of systematic reviews (SRs) and randomized-controlled trials (RCTs) were conducted in five international databases (publication date: 2006-2017). For the medical use of cannabis 16 SRs (of 186 RCTs) were included from a global search and nine further RCTs were comprised from a de novo search. All studies were methodologically assessed.Evidence for the efficacy of cannabis medicine (given as an adjunct to other medication) was found in patients with chronic pain and spasticity due to multiple sclerosis. Benefits were also found for appetite stimulation, improvement of nausea, and weight gain in patients with cancer, HIV/AIDS or in palliative care. Effects were often small. For other physical or mental disorders, only few or no controlled human studies are available. Adverse effects of cannabis medicine are often reported; severe adverse effects were mentioned in single cases only.To provide reliable treatment recommendations for clinicians and patients, more large-sized RCTs with follow-up assessments, consistent outcome measures, and active comparisons are needed.

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy.

N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CNS pathology and lasting neurological benefits. This finding signifies the first successful post-symptomatic treatment of a white matter disorder using an adeno-associated virus vector tailored towards oligodendroglial-restricted transgene expression.

Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief.

Humans and animals are able to associate an environmental cue with the feeling of relief from an aversive event, a phenomenon called relief learning. Relief from an aversive event is rewarding and a relief-associated cue later induces an attenuation of the startle magnitude or approach behavior. Previous studies demonstrated that the nucleus accumbens is essential for relief learning. Here, we asked whether accumbal cannabinoid type 1 (CB1) receptors are involved in relief learning. In rats, we injected the CB1 receptor antagonist/inverse agonist SR141716A (rimonabant) directly into the nucleus accumbens at different time points during a relief learning experiment. SR141716A injections immediately before the conditioning inhibited relief learning. However, SR141716A injected immediately before the retention test was not effective when conditioning was without treatment. These findings indicate that accumbal CB1 receptors play an important role in the plasticity processes underlying relief learning.

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus.

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 +/- and Tsc2 +/- mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 +/- (Eker)-rats express social deficits similar to Tsc2 +/- mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 +/- (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.

Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior.

Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that the pathophysiology of these disorders might derive from aberrations of normal neurodevelopmental changes in the adolescent brain. Understanding the molecular underpinnings of adolescent behavior is therefore critical for understanding the origin of psychopathology, but the molecular mechanisms that trigger adolescent behavior are unknown. Here, we hypothesize that the cannabinoid type-1 receptor (CB1R) may play a critical role in mediating adolescent behavior because enhanced endocannabinoid (eCB) signaling has been suggested to occur transiently during adolescence. To study enhanced CB1R signaling, we introduced a missense mutation (F238L) into the rat Cnr1 gene that encodes for the CB1R. According to our hypothesis, rats with the F238L mutation (Cnr1(F238L)) should sustain features of adolescent behavior into adulthood. Gain of function of the mutated receptor was demonstrated by in silico modeling and was verified functionally in a series of biochemical and electrophysiological experiments. Mutant rats exhibit an adolescent-like phenotype during adulthood compared with wild-type littermates, with typical high risk/novelty seeking, increased peer interaction, enhanced impulsivity, and augmented reward sensitivity for drug and nondrug reward. Partial inhibition of CB1R activity in Cnr1(F238L) mutant rats normalized behavior and led to a wild-type phenotype. We conclude that the activity state and functionality of the CB1R is critical for mediating adolescent behavior. These findings implicate the eCB system as an important research target for the neuropathology of adolescent-onset mental health disorders. SIGNIFICANCE STATEMENT: We present the first rodent model with a gain-of-function mutation in the cannabinoid type-1 receptor (CB1R). Adult mutant rats exhibit an adolescent-like phenotype with typical high risk seeking, impulsivity, and augmented drug and nondrug reward sensitivity. Adolescence is a critical period for suboptimal behavioral choices and the emergence of neuropsychiatric disorders. Understanding the basis of these disorders therefore requires a comprehensive knowledge of how adolescent neurodevelopment triggers behavioral reactions. Our behavioral observations in adult mutant rats, together with reports on enhanced adolescent CB1R signaling, suggest a pivotal role for the CB1R in an adolescent brain as an important molecular mediator of adolescent behavior. These findings implicate the endocannabinoid system as a notable research target for adolescent-onset mental health disorders.

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function.

We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a microRNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient microRNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.

Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: relevance for mental disorders.

Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood. GluA1-containing AMPA receptors, which are located predominantly on hippocampal neurons, are the primary molecular determinants of synaptic plasticity. We investigated here the consequences of the inducible deletion of GluA1 AMPA receptors in glutamatergic neurons during late adolescence. We generated mutant mice with a tamoxifen-inducible deletion of GluA1 under the control of the CamKII promoter for temporally and spatially restricted gene manipulation. GluA1 ablation during late adolescence induced cognitive impairments, but also marked hyperlocomotion and sensorimotor gating deficits. Unlike the global genetic deletion of GluA1, inducible GluA1 ablation during late adolescence resulted in normal sociability. Deletion of GluA1 induced redistribution of GluA2 subunits, suggesting AMPA receptor trafficking deficits. Mutant animals showed increased hippocampal NMDA receptor expression and no change in striatal dopamine concentration. Our data provide new insight into the role of deficient AMPA receptors specifically during late adolescence in inducing several cognitive and behavioral alterations with possible relevance for neuropsychiatric disorders.

Adolescence as a vulnerable period to alter rodent behavior.

Adolescence and puberty are highly important periods for postnatal brain maturation. During adolescence, drastic changes of neuronal architecture and function occur that concomitantly lead to distinct behavioral alterations. Unsurprisingly in view of the multitude of ongoing neurodevelopmental processes in the adolescent brain, most adult neuropsychiatric disorders have their roots exactly during this time span. Adolescence and puberty are therefore crucial developmental periods in terms of understanding the causes and mechanisms of adult mental illness. Valid animal models for adolescent behavior and neurodevelopment might offer better insights into the underlying mechanisms and help to identify specific time windows with heightened susceptibility during development. In order to increase the translational value of such models, we urgently need to define the detailed timing of adolescence and puberty in laboratory rodents. The aim of the present review is to provide a more precise delineation of the time course of these developmental periods during postnatal life in rats and mice and to discuss the impact of adolescence and related neurodevelopmental processes on the heightened susceptibility for mental disorders.

Srgap3⁻/⁻ mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.

Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders.

Impact of pubertal stage at first drink on adult drinking behavior.

BACKGROUND: Early alcohol use is one of the strongest predictors of later alcohol use disorders, with early use usually taking place during puberty. Many researchers have suggested drinking during puberty as a potential biological basis of the age at first drink (AFD) effect. However, the influence of the pubertal phase at alcohol use initiation on subsequent drinking in later life has not been examined so far. METHODS: Pubertal stage at first drink (PSFD) was determined in N = 283 young adults (131 males, 152 females) from an epidemiological cohort study. At ages 19, 22, and 23 years, drinking behavior (number of drinking days, amount of alcohol consumed, hazardous drinking) was assessed using interview and questionnaire methods. Additionally, an animal study examined the effects of pubertal or adult ethanol (EtOH) exposure on voluntary EtOH consumption in later life in 20 male Wistar rats. RESULTS: PSFD predicted drinking behavior in humans in early adulthood, indicating that individuals who had their first drink during puberty displayed elevated drinking levels compared to those with postpubertal drinking onset. These findings were corroborated by the animal study, in which rats that received free access to alcohol during the pubertal period were found to consume more alcohol as adults, compared to the control animals that first came into contact with alcohol during adulthood. CONCLUSIONS: The results point to a significant role of stage of pubertal development at first contact with alcohol for the development of later drinking habits. Possible biological mechanisms and implications for prevention are discussed.

Low income and schizophrenia risk: A narrative review.

Despite decades of research, the precise etiology of schizophrenia is not fully understood. Ample evidence indicates that the disorder derives from a complex interplay of genetic and environmental factors during vulnerable stages of brain maturation. Among the plethora of risk factors investigated, stress, pre- and perinatal insults, and cannabis use have been repeatedly highlighted as crucial environmental risk factors for schizophrenia. Compelling findings from population-based longitudinal studies suggest low income as an additional risk factor for future schizophrenia diagnosis, but underlying mechanisms remain unclear. In this narrative review, we (1) summarize the literature in support of a relationship between low (parental) income and schizophrenia risk, and (2) explore the mediating role of chronic stress, pre- and perinatal factors, and cannabis use as established risk factors for schizophrenia. Our review describes how low income facilitates the occurrence and severity of these established risk factors and thus contributes to schizophrenia liability. The broadest influence of low income was identified for stress, as low income was found to be associated with exposure to a multitude of severe psychological and physiological stressors. This narrative review adds to the growing literature reporting a close relationship between income and mental health.

Longitudinal monitoring of SARS-CoV-2 spike protein-specific antibody responses in Lower Austria.

The Lower Austrian Wachau region was an early COVID-19 hotspot of infection. As previously reported, in June 2020, after the first peak of infections, we determined that 8.5% and 9.0% of the participants in Weißenkirchen and surrounding communities in the Wachau region were positive for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies against the receptor-binding domain of the spike protein of SARS-CoV-2, respectively. Here, we present novel data obtained eight months later (February 2021) from Weißenkirchen, after the second peak of infection, with 25.0% (138/552) and 23.6% (130/552) of participants that are positive for IgG and IgA, respectively. In participants with previous IgG/IgA positivity (June 2020), we observed a 24% reduction in IgG levels, whereas the IgA levels remained stable in February 2021. This subgroup was further analyzed for SARS-CoV-2 induced T cell activities. Although 76% (34/45) and 76% (34/45) of IgG positive and IgA positive participants, respectively, showed specific T cell activities (upon exposure to SARS-CoV-2 spike protein-derived peptides), those were not significantly correlated with the levels of IgG or IgA. Thus, the analyses of antibodies cannot surrogate the measurement of T cell activities. For a comprehensive view on SARS-CoV-2-triggered immune responses, the measurement of different classes of antibodies should be complemented with the determination of T cell activities.

Chronic pubertal cannabinoid treatment as a behavioural model for aspects of schizophrenia: effects of the atypical antipsychotic quetiapine.

Chronic pubertal cannabinoid treatment in rats has been suggested for modelling aspects of schizophrenia since it results in long-lasting behavioural alterations reflecting certain characteristics of schizophrenia symptomatology. Lasting deficits in sensorimotor gating, impaired short-term mnemonic processing, reduced motivation as well as inappropriate and deficient social behaviour have been reported after chronic cannabinod treatment during pubertal development. In addition, sensorimotor gating deficits were able to be restored by acute injections of the typical antipsychotic haloperidol. The aim of this study was to examine possible acute as well as lasting beneficial effects of the atypical antipsychotic drug quetiapine in adult animals undergoing chronic treatment of the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) (1.2 mg/kg) during puberty. Therefore, animals were tested repeatedly for their performance in social interaction and social recognition after acute and chronic quetiapine treatment. Chronic pubertal WIN treatment induced persistent deficits in social recognition and impaired social interaction. Acute quetiapine treatment was able to completely restore those deficits in social behaviour and social memory. Social recognition memory was affected again 1 wk after cessation of chronic quetapine treatment; however, in social interaction persistent improvements could be detected. In conclusion, the results indicate that the atypical antipsychotic drug quetiapine is able to acutely restore deficits in social behaviour induced by developmental cannabinoid exposure and even exert some persistent beneficial effects. Furthermore, the present data give further support and validity for the suitability of chronic pubertal cannabinoid administration as an animal model for aspects of schizophrenia.

Cannabinoid exposure in pubertal rats increases spontaneous ethanol consumption and NMDA receptor associated protein levels.

Recent evidence suggests an involvement of the endocannabinoid system in the regulation of emotional behaviour and ethanol intake. Here we investigated age-specific acute behavioural effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) on anxiety-related behaviour and voluntary ethanol consumption in rats. Animals were treated with WIN (1.2 mg/kg)/vehicle at puberty onset on postnatal day (PD) 40, or at adulthood (PD 100). Animals were tested in the elevated plus-maze (EPM) and the light/dark emergence test (EMT) and for the initial response to alcohol in a free-choice ethanol consumption paradigm. Acute WIN treatment increased anxiety-related behaviours, and this effect was found to be partially more pronounced in pubertal than adult rats. Additionally, increased intake of higher ethanol solutions after cannabinoid treatment was only observed in pubertal rats. These drug-induced behavioural changes during puberty are paralleled by induction of the NR1 subunit of the NMDA receptor in the medial prefrontal cortex and the striatum. Moreover, pubertal but not adult WIN administration increased the levels of the scaffold protein Homer in these brain regions. Enhanced CB1 receptor levels in the reinforcement system were also observed in pubertal compared to adult rats. These data support the notion that puberty is a highly vulnerable period for the aversive effects of cannabinoid exposure. In particular, augmented ethanol intake in pubertal cannabinoid-exposed animals might be related to some extent to increased emotional behaviour and in particular to enhanced NMDA and CB1 receptor signalling.

Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats.

There is a strong association between autism spectrum disorders (ASD), epilepsy and intellectual disability in humans, but the nature of these correlations is unclear. The monogenic disorder Tuberous Sclerosis Complex (TSC) has high rates of ASD, epilepsy and cognitive deficits. Here we used the Tsc2 (+/-) (Eker) rat model of TSC and an experimental epilepsy paradigm to study the causal effect of seizures on learning and memory and social behavior phenotypes. Status epilepticus was induced by kainic acid injection at P7 and P14 in wild-type and Tsc2 (+/-) rats. At the age of 3-6 months, adult rats were assessed in the open field, light/dark box, fear conditioning, Morris water maze, novel object recognition and social interaction tasks. Learning and memory was unimpaired in naïve Tsc2 (+/-) rats, and experimental epilepsy did not impair any aspects of learning and memory in either wild-type or Tsc2 (+/-) rats. In contrast, rearing in the open field, novel object exploration and social exploration was reduced in naïve Tsc2 (+/-) rats. Seizures induced anxiety and social evade, and reduced social exploration and social contact behavior in wild-type and Tsc2 (+/-) rats. Our study shows that Tsc2 haploinsufficiency and developmental status epilepticus in wild-type and Tsc2 (+/-) rats independently lead to autistic-like social deficit behaviors. The results suggest that the gene mutation may be sufficient to lead to some social deficits, and that seizures have a direct and additive effect to increase the likelihood and range of autistic-like behaviors.

Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine.

The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.