Manipulation of α4ßδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism.

Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4ßδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4ßδ receptors also increase at puberty in L3 PL (P < 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4ßδ, reduced L3 spine density by half (P < 0.0001), while α4 knock-out increased spine density âˆ¼ 40 % (P < 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: -0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; -0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P < 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4ßδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders.

Increased Dendritic Branching of and Reduced δ-GABAA Receptor Expression on Parvalbumin-Positive Interneurons Increase Inhibitory Currents and Reduce Synaptic Plasticity at Puberty in Female Mouse CA1 Hippocampus.

Parvalbumin positive (PV+) interneurons play a pivotal role in cognition and are known to be regulated developmentally and by ovarian hormones. The onset of puberty represents the end of a period of optimal learning when impairments in synaptic plasticity are observed in the CA1 hippocampus of female mice. Therefore, we tested whether the synaptic inhibitory current generated by PV+ interneurons is increased at puberty and contributes to these deficits in synaptic plasticity. To this end, the spontaneous inhibitory postsynaptic current (sIPSC) was recorded using whole-cell patch-clamp techniques from CA1 pyramidal cells in the hippocampal slice before (PND 28-32) and after the onset of puberty in female mice (~PND 35-44, assessed by vaginal opening). sIPSC frequency and amplitude were significantly increased at puberty, but these measures were reduced by 1 µM DAMGO [1 µM, (D-Ala2, N-MePhe4, Gly-ol)-enkephalin], which silences PV+ activity via µ-opioid receptor targets. At puberty, dendritic branching of PV+ interneurons in GAD67-GFP mice was increased, while expression of the δ subunit of the GABAA receptor (GABAR) on these interneurons decreased. Both frequency and amplitude of sIPSCs were significantly increased in pre-pubertal mice with reduced δ expression, suggesting a possible mechanism. Theta burst induction of long-term potentiation (LTP), an in vitro model of learning, is impaired at puberty but was restored to optimal levels by DAMGO administration, implicating inhibition via PV+ interneurons as one cause. Administration of the neurosteroid/stress steroid THP (30 nM, 3α-OH, 5α-pregnan-20-one) had no effect on sIPSCs. These findings suggest that phasic inhibition generated by PV+ interneurons is increased at puberty when it contributes to impairments in synaptic plasticity. These results may have relevance for the changes in cognitive function reported during early adolescence.

Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action.

UNLABELLED: Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal "no-go" pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OEdev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization. SIGNIFICANCE STATEMENT: Motivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease.

Striatal dopamine type 2 receptor availability in anorexia nervosa.

The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [(11)C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [(11)C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance.

Adolescent risk factors for purging in young women: findings from the national longitudinal study of adolescent health.

BACKGROUND: There exists a dearth of prospective adolescent eating disorder studies with samples that are large enough to detect small or medium sized effects for risk factors, that are generalizable to the broader population, and that follow adolescents long enough to fully capture the period of development when the risk of eating disorder symptoms occurring is highest. As a result, the purpose of this study was to examine psychosocial risk factors for purging for weight control in a nationally representative sample of adolescents. Data were extracted from the restricted-use data sets of the National Longitudinal Study of Adolescent Health (Waves I-III), selecting females with valid demographic and purging information (N = 5,670). RESULTS: The prevalence of purging was 0.88% at Wave II and 0.56% at Wave III. In multivariable multinomial logistic regressions, purging at Wave II was predicted by parental poverty and low levels of self-esteem at Wave I; purging at Wave III was predicted by body mass index and the frequency of delinquent behaviors at Wave I. CONCLUSIONS: Individuals with high body mass index, individuals with low self-esteem, and individuals in families experiencing economic hardship appear specifically at risk for the development of purging behaviors in later years and may benefit from more targeted prevention efforts.

Prevalence and correlates of unhealthy weight control behaviors: findings from the national longitudinal study of adolescent health.

BACKGROUND: A recent study examined the prevalence, clinical correlates, age trends, and stability of unhealthy weight control behaviors (UWCB; purging and diet pill use) in a nationally representative sample of Norwegian boys and girls. The purpose of this study was to provide similar, comparative analyses for a nationally representative sample of American youth. METHODS: Data were extracted from the restricted use data files of survey Waves I, II, and III of the National Longitudinal Study of Adolescent Health (Add Health), selecting all participants who at Wave I had provided information on age, sex, and UWCB. Using UWCB information, three groups were created (purging, diet pill use, and no recent UWCB "controls") and compared on indicators of adverse health or mental health. RESULTS: Girls consistently were more likely than boys to report UWCB. UWCB were significantly associated with higher body mass index, self-perception of being overweight, low self-esteem, depression, and delinquency. Prevalence estimates for purging remained relatively constant across the three survey waves; in contrast, diet pill use was especially common at Wave III. CONCLUSIONS: Age trends, gender differences, and clinical correlates of change in the likelihood of UWCB between Waves I-III were all identified in analyses comparing purging and diet pill use in American adolescents. Females and older adolescents were specifically more likely to engage in pill use than purging, and individuals with increased weight dissatisfaction, a history of delinquent behaviors, more depression symptoms, or lower self-esteem were more likely to engage in an unhealthy weight control behavior over time. While the Norwegian study found that prevalence of purging was lower among young adult participants, our results suggested that there were no significant differences in prevalence between age groups.