Administration of Atosiban, an oxytocin receptor antagonist, ameliorates autistic-like behaviors in a female rat model of valproic acid-induced autism.

Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat's model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.

Urolithin A Inhibits Anterior Basolateral Amygdala to Ventral Hippocampal CA1 Circuit to Ameliorate Amyloid-ß-Impaired Social Ability.

Background: Anxiety and social withdrawal are highly prevalent among patients with Alzheimer's disease (AD). However, the neural circuit mechanisms underlying these symptoms remain elusive, and there is a need for effective prevention strategies. Objective: This study aims to elucidate the neural circuitry mechanisms underlying social anxiety in AD. Methods: We utilized 5xFAD mice and conducted a series of experiments including optogenetic manipulation, Tandem Mass Tag-labeled proteome analysis, behavioral assessments, and immunofluorescence staining. Results: In 5xFAD mice, we observed significant amyloid-ß (Aß) accumulation in the anterior part of basolateral amygdala (aBLA). Behaviorally, 6-month-old 5xFAD mice displayed excessive social avoidance during social interaction. Concurrently, the pathway from aBLA to ventral hippocampal CA1 (vCA1) was significantly activated and exhibited a disorganized firing patterns during social interaction. By optogenetically inhibiting the aBLA-vCA1 pathway, we effectively improved the social ability of 5xFAD mice. In the presence of Aß accumulation, we identified distinct changes in the protein network within the aBLA. Following one month of administration of Urolithin A (UA), we observed significant restoration of the abnormal protein network within the aBLA. UA treatment also attenuated the disorganized firings of the aBLA-vCA1 pathway, leading to an improvement in social ability. Conclusions: The aBLA-vCA1 circuit is a vulnerable pathway in response to Aß accumulation during the progression of AD and plays a crucial role in Aß-induced social anxiety. Targeting the aBLA-vCA1 circuit and UA administration are both effective strategies for improving the Aß-impaired social ability.

Angiotensin II involvement in the development and persistence of amphetamine-induced sensitization: Striatal dopamine reuptake implications.

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT1-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1-R blockade altered the performance of social interaction. Our results highlight the AT1-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.

Bumetanide in autism spectrum disorder / Bumetanida no transtorno do espectro autista / Bumetanida en el trastorno del espectro autista

Objectives: This study aimed to make a bibliographic update on the already published data on bumetanide, addressing the main information on its use in Autism Spectrum Disorder (ASD). Methods: This was an integrative narrative review in which the following databases were used: Web of Science, MEDLINE, ScienceDirect, and Scielo. The descriptors used were: Autism Spectrum Disorder, Autistic Disorder and Bumetanide. It was considered only articles published in English and French. Original articles, randomized clinical trials, case reports, and review articles were included. Results: The results show that the use of bumetanide alters regions of the brain linked to the positive development of language, improvement of visual contact, improvement in social interactions, among others. Studies are also concerned about the safety and efficacy of bumetanide in ASD since several adverse effects have been reported. The most frequent were hypokalemia, polyuria, and loss of appetite. Conclusion: Bumetanide has proven as effective in improving some important symptoms in ASD, especially linked to language and social interaction, however, studies with larger groups of patients and with longer treatment and observation time are needed to confirm the efficacy and clarify the safety profile in use for people with ASD.

Objetivo: O objetivo deste trabalho foi fazer uma atualização bibliográfica sobre os dados já publicados da bumetanida, abordando as principais informações sobre seu uso no Transtorno do Espectro Autista (TEA). Metodologia: Foi realizada uma revisão do tipo narrativa integrativa, da qual foram utilizadas as bases de dados: Web of Science, MEDLINE, ScienceDirect e Scielo, com a utilização dos seguintes descritores: Autism Spectrum Disorder, Autistic Disorder e Bumetanide. Foram considerados apenas artigos publicados nas línguas inglesa e francesa. Foram incluídos artigos originais, ensaios clínicos randomizados e relatos de caso. Foram excluídos artigos de revisão. Resultados: Os resultados mostram que o uso da bumetanida altera regiões do cérebro ligadas ao desenvolvimento positivo da linguagem, melhora do contato visual, melhora nas interações sociais, entre outros. Os estudos também se preocupam em relacionar a segurança e a eficácia da bumetanida no TEA, do qual foram relatados diversos efeitos adversos, sendo os mais frequentes a hipocalemia, a poliúria e a perda de apetite. Conclusão: A bumetanida mostrou ser eficaz na melhoria de alguns importantes sintomas no TEA, especialmente ligados à linguagem e interação social, entretanto, estudos com grupos maiores de pacientes e com maior tempo de tratamento e observação são necessários para confirmar a eficácia e esclarecer o perfil de segurança no uso para pessoas com TEA.

: Este estudio tuvo como objetivo realizar una actualización bibliográfica sobre los datos ya publicados sobre la bumetanida, abordando la principal información sobre su uso en el Trastorno del Espectro Autista (TEA). Métodos: Se trata de una revisión narrativa integradora en la que se utilizaron las siguientes bases de datos: Web of Science, MEDLINE, ScienceDirect y Scielo. Los descriptores utilizados fueron: Trastorno del Espectro Autista, Trastorno Autista y Bumetanida. Se consideraron sólo los artículos publicados en inglés y francés. Se incluyeron artículos originales, ensayos clínicos aleatorios, informes de casos y artículos de revisión. Resultados: Los resultados muestran que el uso de la bumetanida altera regiones del cerebro relacionadas con el desarrollo positivo del lenguaje, la mejora del contacto visual, la mejora de las interacciones sociales, entre otros. Los estudios también se preocupan por la seguridad y eficacia de la bumetanida en el TEA, ya que se han reportado varios efectos adversos. Los más frecuentes fueron la hipocalemia, la poliuria y la pérdida de apetito. Conclusiones: La bumetanida ha demostrado ser eficaz en la mejora de algunos síntomas importantes en el TEA, especialmente vinculados al lenguaje y la interacción social, sin embargo, se necesitan estudios con grupos más grandes de pacientes y con mayor tiempo de tratamiento y observación para confirmar la eficacia y aclarar el perfil de seguridad en el uso para personas con TEA.

Alpha-melanocyte-stimulating hormone (αMSH) modulates the rewarding properties of social interactions in an oxytocin receptor-dependent manner in Syrian hamsters (Mesocricetus Auratus).

A reduction in the rewarding properties of social interactions is frequently a key contributor to neuropsychiatric disorders. Although much remains to be learned about the neural mechanisms governing social reward, numerous studies have found that oxytocin can enhance the salience of rewarding social interactions. As a result, oxytocin has been suggested as a pharmacotherapy for disorders characterized by a dampening of social motivation. However, exogenous oxytocin does not cross the blood-brain barrier effectively, which has led to the investigation of alternative approaches to induce central oxytocin release, such as pharmaceuticals targeting melanocortins. Although oxytocin treatment is widely viewed to increase social reward, there is also recent evidence that high concentrations of oxytocin can decrease social reward. In the present study we tested the hypothesis that alpha-melanocyte-stimulating hormone (αMSH) influences the rewarding properties of social interactions by acting on oxytocin receptors. Male and female Syrian hamsters were given intracerebroventricular infusions of saline, αMSH, or a cocktail containing αMSH and an oxytocin receptor antagonist during social conditioning with a same-sex hamster and then tested for a conditioned place preference. αMSH decreased preference for the socially-paired chamber compared to saline treatment, and administration of the oxytocin antagonist concurrent with αMSH administration returned subjects' preference to control levels. Importantly, αMSH treatments did not affect any measures of body composition or the specific social behaviors displayed during conditioning. These data suggest that melanocortin-targeting drugs should be administered carefully to avoid the possibility of decreasing the rewarding properties of social interactions.

Effects of galantamine on social interaction impairments in cholecystokinin receptor-2 overexpression mice.

We examined whether galantamine (GAL), a cholinesterase inhibitor and allosteric potentiating ligand for α7 nicotinic acetylcholine receptor (nAChR), had an impact on emotional abnormalities in forebrain-specific cholecystokinin receptor-2 overexpressed transgenic mice. Treatment with GAL (1 mg/kg, s.c.) attenuated the decrease of social interaction time, but failed to attenuate anxiety-like behavior in the elevated plus-maze test. The effect of GAL was blocked by an α7 nAChR antagonist, methyllycaconitine (3 mg/kg, i.p.). These results suggest that GAL improved social interaction impairments via α7 nAChR and could be useful to treat sociability-related emotional abnormalities.

Ameliorating effect of continuous alpha-glycosyl isoquercitrin treatment starting from late gestation in a rat autism model induced by postnatal injection of lipopolysaccharides.

The present study investigated the role of neuroinflammation and brain oxidative stress induced by neonatal treatment with lipopolysaccharides (LPS) on the development of autism spectrum disorder (ASD)-like behaviors and disruptive hippocampal neurogenesis in rats by exploring the chemopreventive effects of alpha-glycosyl isoquercitrin (AGIQ) as an antioxidant. AGIQ was dietary administered to dams at 0.25% or 0.5% (w/w) from gestational day 18 until postnatal day (PND) 21 on weaning and then to pups until the adult stage on PND 77. The pups were intraperitoneally injected with LPS (1 mg/kg body weight) on PND 3. At PND 6, LPS alone increased Iba1+ and CD68+ cell numbers without changing the CD163+ cell number and strongly upregulated pro-inflammatory cytokine gene expression (Il1a, Il1b, Il6, Nfkb1, and Tnf) in the hippocampus, and increased brain malondialdehyde levels. At PND 10, pups decreased ultrasonic vocalization (USV), suggesting the induction of pro-inflammatory responses and oxidative stress to trigger communicative deficits. By contrast, LPS alone upregulated Nfe2l2 expression at PND 6, increased Iba1+, CD68+, and CD163+ cell numbers, and upregulated Tgfb1 at PND 21, suggesting anti-inflammatory responses until the weaning period. However, LPS alone disrupted hippocampal neurogenesis at weaning and suppressed social interaction parameters and rate of freezing time at fear acquisition and extinction during the adolescent stage. On PND 77, neuroinflammatory responses had mostly disappeared; however, disruptive neurogenesis and fear memory deficits were sustained. AGIQ ameliorated most changes on acute pro-inflammatory responses and oxidative stress at PND 6, and the effects on USVs at PND 10 and neurogenesis and behavioral parameters throughout the adult stage. These results suggested that neonatal LPS treatment induced acute but transient neuroinflammation, triggering the progressive disruption of hippocampal neurogenesis leading to abnormal behaviors in later life. AGIQ treatment was effective for ameliorating LPS-induced progressive changes by critically suppressing initial pro-inflammatory responses and oxidative stress.

Discontinuation and remission rates and social functioning in patients with schizophrenia receiving second-generation antipsychotics: 52-week evaluation of JUMPs, a randomized, open-label study.

AIM: Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin. CONCLUSION: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.

Increasing Central Serotonin with 5-hydroxytryptophan Disrupts the Inhibition of Social Gaze in Nonhuman Primates.

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted amongst patient populations treated with serotonergic drugs. However, those in the field lack a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques (both sexes) to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on their gaze responses, making them worse at flexibly switching between orienting and inhibiting behaviors. Furthermore, the effects of 5-HTP on performance correlated with a constriction of the pupil, an increased time to initiate trials, and an increased reaction time, suggesting that the disruptive effects of 5-HTP on social gaze behaviors are likely driven by a downregulation of arousal and motivational states. Together, these findings provide causal evidence for a modulatory relationship between 5-HTP and social gaze behaviors in nonhuman primates and offer translational insights for the role of the serotonergic system in social gaze.SIGNIFICANCE STATEMENT Behavioral changes arising from pharmacological agents that target serotonergic functions are complex and difficult to predict. Here, we examined the causal impacts of administering the direct precursor of serotonin, 5-HTP, on orienting and inhibiting social gaze in nonhuman primates. 5-HTP increased central concentrations of serotonin and selectively impaired the ability of monkeys to inhibit orienting to faces while similarly impairing the ability of monkeys to orient to face and control images. These behavioral gaze impairments were systematically associated with a downregulation of arousal and motivational states, indexed by pupil constriction, increased time to initiate trials, and increased reaction time. These findings provide a causal link between 5-HTP and social gaze behaviors in nonhuman primates and provide translational insights about serotonergic interventions.

Lack of evidence for positive reinforcing and prosocial effects of MDMA in pair-housed male and female rats.

3,4-Methylenedioxymethamphetamine (MDMA) is classified as an entactogen, producing feelings of emotional openness and relatedness. One unique feature of MDMA is that people tend to selectively take this drug in social and/or intimate situations. Although MDMA is recognized as having abuse liability, preclinical studies report that it has weak reinforcing effects in animals. The objective of this study was to characterize the positive reinforcing and prosocial effects of MDMA in a translational model of the social environment in which two rats have simultaneous and contingent access to MDMA in close physical proximity. To this end, MDMA self-administration was examined on both fixed and progressive ratio schedules of reinforcement in six groups of rats: (1) isolated males, (2) isolated females, (3) male-male dyads, (4) female-female dyads, (5) male-female dyads, and (6) female-male dyads. For pair-housed rats, data from both rats were analyzed. Next, social preferences were examined in a partner preference test. MDMA failed to produce positive reinforcing effects under all conditions examined. Across a 30-fold dose range (0.01-1.0 mg/kg/infusion), MDMA did not maintain higher responding than saline on both schedules of reinforcement and in all groups tested. In partner preference tests, a history of shared exposure to MDMA did not establish a social preference, and acute administration of MDMA failed to establish a preference for another MDMA-treated rat. These data suggest that social contact does not increase the positive reinforcing effects of MDMA in rats, and that neither contingent nor noncontingent MDMA administration establishes a social preference in rats.

Septal cholinergic input to CA2 hippocampal region controls social novelty discrimination via nicotinic receptor-mediated disinhibition.

Acetylcholine (ACh), released in the hippocampus from fibers originating in the medial septum/diagonal band of Broca (MSDB) complex, is crucial for learning and memory. The CA2 region of the hippocampus has received increasing attention in the context of social memory. However, the contribution of ACh to this process remains unclear. Here, we show that in mice, ACh controls social memory. Specifically, MSDB cholinergic neurons inhibition impairs social novelty discrimination, meaning the propensity of a mouse to interact with a novel rather than a familiar conspecific. This effect is mimicked by a selective antagonist of nicotinic AChRs delivered in CA2. Ex vivo recordings from hippocampal slices provide insight into the underlying mechanism, as activation of nAChRs by nicotine increases the excitatory drive to CA2 principal cells via disinhibition. In line with this observation, optogenetic activation of cholinergic neurons in MSDB increases the firing of CA2 principal cells in vivo. These results point to nAChRs as essential players in social novelty discrimination by controlling inhibition in the CA2 region.

Resveratrol Attenuates Learning, Memory, and Social Interaction Impairments in Rats Exposed to Arsenic.

Arsenic (As) toxicity has deleterious effects on human health causing disorder in the brain. The aim of this study was to investigate the possible neuroprotective effect of resveratrol (RSV) on arsenic-induced neurotoxicity in rats. Neurotoxicity in rats was developed by treating As 10 mg/kg/day for 21 days orally. Animals were put into seven groups: control, vehicle, As, As+RSV10, As+RSV20 mg/kg, RSV10, and RSV20 mg/kg. Behavioral assessments such as the social interaction test, novel object recognition test, elevated plus maze, open field, the Morris water maze, in addition to assessment of biomarkers such as ferric reducing ability of plasma assay, glutathione assay, and malondialdehyde assay, were used to evaluate the effects of RSV on cognitive impairment and molecular changes induced by As. The results showed that cognitive performance impaired in As rats. RSV20 mg/kg significantly could ameliorate behavioral changes like spatial learning in days 3 and 4 (p < 0.05), recognition learning and memory (p < 0.01), disabilities in motor coordination and stress (p < 0.05), increased anxiety (p < 0.05), and social interaction deficit (sociability (p < 0.001) and social memory (p < 0.05)). RSV20 mg/kg also attenuated molecular modifications like decreased antioxidant power (p < 0.001), reduced glutathione content (p < 0.05), and increased malondialdehyde level (p < 0.05) induced by As. In addition to oxidative stress assessments, RSV10 mg/kg could significantly increase FRAP (p < 0.01) and GSH (p < 0.05); however, MDA was not significantly increased. Our current behavioral findings suggest that RSV has neuroprotective effects against AS toxicity.

Effects of Dopamine D1-Like Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys.

Although dopamine plays a prominent role in mediating cocaine's abuse-related effects, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2Rs) have been characterized, less is known about dopamine D1-like receptors (D1Rs). The present experiments examined the effects of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status influenced the behavioral effects of D1R-acting drugs. The high-efficacy D1R agonist SKF 81297, low-efficacy D1R agonist SKF 38393, and D1R antagonist SCH 23390 were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine-choice dose-effect curve was determined daily. To assess selectivity of behavioral effects on cocaine choice, effects of doses that did not disrupt responding (indicated by a ≥35% decrease in total reinforcers delivered) were analyzed. Neither SKF 81297 nor SCH 23390 affected cocaine choice in dominant or subordinate monkeys. However, the low-efficacy agonist SKF 38393 selectively decreased cocaine choice; this effect was larger and only reached statistical significance in subordinate monkeys. Increasing the time between D1-acting drug administration and the cocaine choice session did not affect these results. The results indicate that, like D2R-acting drugs, the behavioral effects of D1R-acting drugs on cocaine choice can vary according to intrinsic efficacy and social status. Moreover, they demonstrate that D1R-acting drugs affect behavior under a narrower range of conditions than D2R-acting drugs. SIGNIFICANCE STATEMENT: Cocaine use disorder represents an insidious public health concern with no Food and Drug Administration-approved medications. Although dopamine receptors have been strongly implicated in mediating the abuse-related effects of cocaine, the roles of dopamine receptor subtypes are incompletely understood. The present study in nonhuman primates found that cocaine choice was decreased only by a low-efficacy D1R agonist, and that this effect depended on the social status of the monkey.

Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin.

The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.

Glutamate Delta-1 Receptor Regulates Inhibitory Neurotransmission in the Nucleus Accumbens Core and Anxiety-Like Behaviors.

Glutamate delta-1 receptor (GluD1) is a member of the ionotropic glutamate receptor family expressed at excitatory synapses and functions as a synaptogenic protein by interacting with presynaptic neurexin. We have previously shown that GluD1 plays a role in the maintenance of excitatory synapses in a region-specific manner. Loss of GluD1 leads to reduced excitatory neurotransmission in medium spiny neurons (MSNs) in the dorsal striatum, but not in the ventral striatum (both core and shell of the nucleus accumbens (NAc)). Here, we found that GluD1 loss leads to reduced inhibitory neurotransmission in MSNs of the NAc core as evidenced by a reduction in the miniature inhibitory postsynaptic current frequency and amplitude. Presynaptic effect of GluD1 loss was further supported by an increase in paired pulse ratio of evoked inhibitory responses indicating reduced release probability. Furthermore, analysis of GAD67 puncta indicated a reduction in the number of putative inhibitory terminals. The changes in mIPSC were independent of cannabinoid or dopamine signaling. A role of feed-forward inhibition was tested by selective ablation of GluD1 from PV neurons which produced modest reduction in mIPSCs. Behaviorally, local ablation of GluD1 from NAc led to hypolocomotion and affected anxiety- and depression-like behaviors. When GluD1 was ablated from the dorsal striatum, several behavioral phenotypes were altered in opposite manner compared to GluD1 ablation from NAc. Our findings demonstrate that GluD1 regulates inhibitory neurotransmission in the NAc by a combination of pre- and postsynaptic mechanisms which is critical for motor control and behaviors relevant to neuropsychiatric disorders.

A prophylactic effect of macrophage-colony stimulating factor on chronic stress-induced depression-like behaviors in mice.

Innate immune activation has been shown to reduce the severity of nervous system disorders such as brain ischemia and traumatic brain damage. Macrophage-colony stimulating factor (M-CSF), a drug that is used to treat hematological system disease, is an enhancer of the innate immune response. In the present study, we evaluated the effect of M-CSF preconditioning on chronic social defeat stress (CSDS)-induced depression-like behaviors in mice. Results showed that a single M-CSF injection 1 day before stress exposure at the dose of 100 and 500 µg/kg, or a single M-CSF injection (100 µg/kg) 1 or 5 days but not 10 days before stress exposure prevented CSDS-induced depression-like behaviors in mice. Further analysis showed that a second M-CSF injection 10 days after the first M-CSF injection and a 2 × or 4 × M-CSF injections 10 days before stress exposure also prevented CSDS-induced depression-like behaviors. Molecular studies revealed that a single M-CSF injection prior to stress exposure skewed the neuroinflammatory responses in the brain in CSDS-exposed mice towards an anti-inflammatory phenotype. These behavioral and molecular actions of M-CSF were correlated with innate immune stimulation, as pre-inhibiting the innate immune activation by minocycline pretreatment (40 mg/kg) abrogated the preventive effect of M-CSF on CSDS-induced depression-like behaviors and neuroinflammatory responses. These results provide evidence to show that innate immune activation by M-CSF pretreatment may prevent chronic stress-induced depression-like behaviors via preventing the development of neuroinflammatory response in the brain, which may help to develop novel strategies for the prevention of depression.

Oxytocin administration modulates the complex type of ultrasonic vocalisation of mice pups prenatally exposed to valproic acid.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by communication disability with no curative treatment. Maternal separation-induced ultrasonic vocalisation (USV) was widely used to assess communication disability between pups and dams. Particularly, USV calls in many genetically modified ASD model mice were altered. Previously, we demonstrated that mice pups exposed to valproic acid in utero (VPA pups) showed decreased number of USV calls on postnatal day 11 and were rescued by subcutaneous injection of oxytocin. However, the qualitative change of USV calls by oxytocin has not been evaluated in VPA pups. In the present study, we examined the duration of oxytocin effect and analysed the altered pattern of USV calls using VPA pups. The oxytocin administration increased the total number of USV calls and the effect persisted up to 120 min in VPA pups. The pattern analysis revealed that the increase in the number of complex calls also persisted up to 120 min. These results suggested that oxytocin had a prolonged effect on USV calls, mainly on complex calls, in VPA pup, showing that oxytocin could recover their social modality to respond to maternal separation.

Ilex kudingcha C.J. Tseng Mitigates Phenotypic Characteristics of Human Autism Spectrum Disorders in a Drosophila Melanogaster Rugose Mutant.

Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Tseng is a nootropic botanical used in Asia for neuroprotection and improvement of cognition. This study establishes that a chemically characterized extract from IK (IKE) mitigates behavioral traits in the Drosophila melanogaster rugose mutant, whose traits resemble human ASD, and examines possible mechanisms. IKE treatment significantly ameliorated deficits in social interaction, short-term memory, and locomotor activity in Drosophila rugose, and significantly increased synaptic bouton number of size more than 2 µm2 in the neuromuscular junctions (NMJs) of Drosophila rugose. To clarify mechanism(s) of IKE action, methylphenidate (MPH), a dopamine transporter inhibitor, was included as a reference drug in the behavioral assays: MPH significantly improved social interaction and short-term memory deficit in Drosophila rugose; administration of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist sulpiride reversed the ameliorative effects of both MPH and IKE on the social interaction deficits of Drosophila rugose. To extend analysis of IKE treatment to the vertebrate central nervous system, ASD-associated gene expression in mouse hippocampus was studied by RNA-seq: IKE treatment altered the expression of genes coding phosphoinositide 3-kinases/protein kinase B (PI3K-Akt), proteins in glutamatergic, dopaminergic, serotonergic, and GABAergic synapses, cAMP response element-binding protein (CREB), and RNA transporter proteins. These results provide a foundation for further analysis of IKE as a candidate for treatment of some forms of ASD.