Synaptic cell-adhesion molecule latrophilin-2 is differentially directed to dendritic domains of hippocampal neurons.

Hippocampal pyramidal cells possess elaborate dendritic arbors with distinct domains that are targeted with input-specific synaptic sites. This synaptic arrangement is facilitated by synaptic cell-adhesion molecules that act as recognition elements to connect presynaptic and postsynaptic neurons. In this study, we investigate the organization of the synaptic recognition molecule latrophilin-2 at the surface of pyramidal neurons classified by spatial positioning and action potential firing patterns. Surveying two hippocampal neurons that highly express latrophilin-2, late-bursting CA1 pyramidal cells and early-bursting subiculum pyramidal cells, we found the molecule to be differentially positioned on their respective dendritic compartments. Investigating this latrophilin-2 positioning at the synaptic level, we found that the molecule is not present within either the pre- or postsynaptic terminal but rather is tightly coupled to synapses at a perisynaptic location. Together these findings indicate that hippocampal latrophilin-2 distribution patterning is cell-type specific, and requires multiple postsynaptic neurons for its synaptic localization.

Enhancing the ATra Black Box Matching Algorithm: Use of All Names for Deduplication Across Jurisdictions.

OBJECTIVES: Achieving accurate, timely, and complete HIV surveillance data is complicated in the United States by migration and care seeking across jurisdictional boundaries. To address these issues, public health entities use the ATra Black Box-a secure, electronic, privacy-assuring system developed by Georgetown University-to identify and confirm potential duplicate case records, exchange data, and perform other analytics to improve the quality of data in the Enhanced HIV/AIDS Reporting System (eHARS). We aimed to evaluate the ability of 2 ATra software algorithms to identify potential duplicate case-pairs across 6 jurisdictions for people living with diagnosed HIV. METHODS: We implemented 2 matching algorithms for identifying potential duplicate case-pairs in ATra software. The Single Name Matching Algorithm examines only 1 name for a person, whereas the All Names Matching Algorithm examines all names in eHARS for a person. Six public health jurisdictions used the algorithms. We compared outputs for the overall number of potential matches and changes in matching level. RESULTS: The All Names Matching Algorithm found more matches than the Single Name Matching Algorithm and increased levels of match. The All Names Matching Algorithm identified 9070 (4.5%) more duplicate matches than the Single Name Matching Algorithm (n = 198 828) and increased the total number of matches at the exact through high levels by 15.4% (from 167 156 to 192 932; n = 25 776). CONCLUSIONS: HIV data quality across multiple jurisdictions can be improved by using all known first and last names of people living with diagnosed HIV that match with eHARS rather than using only 1 first and last name.

Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation.

The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. Currently, the influence of these oncoproteins on the global regulation of the host proteome is not well defined. Liquid chromatography coupled with quantitative tandem mass spectrometry using isobaric-tagged peptides was used to investigate the effects of the HPV16 oncoproteins E6 and E7 on protein levels in human neonatal keratinocytes (HEKn). Pathway and gene ontology enrichment analyses revealed that the cells expressing the HPV oncoproteins have elevated levels of proteins related to interferon response, inflammation and DNA damage response, while the proteins related to cell organization and epithelial development are downregulated. This study identifies dysregulated pathways and potential biomarkers associated with HPV oncoproteins in primary keratinocytes which may have therapeutic implications. Most notably, DNA damage response pathways, DNA replication, and interferon signaling pathways were affected in cells transduced with HPV16 E6 and E7 lentiviruses. Moreover, proteins associated with cell organization and differentiation were significantly downregulated in keratinocytes expressing HPV16 E6 + E7. High-risk HPV E6 and E7 oncoproteins are necessary for the HPV-associated transformation of keratinocytes. However their influence on the global dysregulation of keratinocyte proteome is not well documented. Here shotgun proteomics using TMT-labeling detected over 2500 significantly dysregulated proteins associated with E6 and E7 expression. Networks of proteins related to interferon response, inflammation and DNA damage repair pathways were altered.

Parahippocampal latrophilin-2 (ADGRL2) expression controls topographical presubiculum to entorhinal cortex circuit connectivity.

Brain circuits are comprised of distinct interconnected neurons that are assembled by synaptic recognition molecules presented by defined pre- and post-synaptic neurons. This cell-cell recognition process is mediated by varying cellular adhesion molecules, including the latrophilin family of adhesion G-protein-coupled receptors. Focusing on parahippocampal circuitry, we find that latrophilin-2 (Lphn2; gene symbol ADGRL2) is specifically enriched in interconnected subregions of the medial entorhinal cortex (MEC), presubiculum (PrS), and parasubiculum (PaS). Retrograde viral tracing from the Lphn2-enriched region of the MEC reveals unique topographical patterning of inputs arising from the PrS and PaS that mirrors Lphn2 expression. Using a Lphn2 conditional knockout mouse model, we find that deletion of MEC Lphn2 expression selectively impairs retrograde viral labeling of inputs arising from the ipsilateral PrS. Combined with analysis of Lphn2 expression within the MEC, this study reveals Lphn2 to be selectively expressed by defined cell types and essential for MEC-PrS circuit connectivity.

Metastatic Donor-derived Malignancies Following Simultaneous Pancreas-kidney Transplant: Three Case Reports and Management Strategies.

Stopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient's immune system will allow "rejection" of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient's allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision. METHODS: The charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature. RESULTS: Consistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years. CONCLUSION: The successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.

Trends in Living Donation by Race and Ethnicity Among Children With End-stage Renal Disease in the United States, 1995-2015.

BACKGROUND: Living donor kidney transplants have declined among adults with end-stage renal disease (ESRD), with increases in racial/ethnic disparities over time. Secular trends in racial/ethnic disparities in living donor kidney transplantation have not been well studied in children. METHODS: Using multivariable Cox modeling, we examined changes in living donor kidney transplant rates over time and probability of receiving living donor kidney transplantation within 2 years of incident ESRD by race/ethnicity among 19 772 children in the US Renal Data System, 1995-2015. We also examined racial/ethnic concordance between donors and recipients. RESULTS: Overall, living donor kidney transplant rates declined by 3% annually since 1995 for all racial/ethnic groups except Asians for whom living donor kidney transplant rates remained stable; however, disparities persist. Compared with non-Hispanic white children, Hispanics were 42% less likely (adjusted hazard ratio: 0.58; 95% confidence interval: 0.49-0.67), Asians 39% less likely (0.61; 0.47-0.79), and blacks 66% less likely (0.34; 0.28-0.42) to receive living kidney donor transplantation within 2 years, even when accounting for deceased donor transplantation as a competing risk. Additionally, while 95% of non-Hispanic white children had non-Hispanic white donors, only 56% of Asian recipients had Asian donors (P < 0.001). Asian recipients were more likely to have nonrelated donors (P < 0.001). CONCLUSIONS: There are ongoing declines in living donation for children with ESRD for uncertain reasons, and minority populations experience significantly reduced access to timely living donor transplant, even when accounting for changes in deceased donation and donor-recipient relationships.

Lymphatic-to-blood vessel transition in adult microvascular networks: A discovery made possible by a top-down approach to biomimetic model development.

OBJECTIVE: Emerging areas of vascular biology focus on lymphatic/blood vessel mispatterning and the regulation of endothelial cell identity. However, a fundamental question remains unanswered: Can lymphatic vessels become blood vessels in adult tissues? Leveraging a novel tissue culture model, the objective of this study was to track lymphatic endothelial cell fate over the time course of adult microvascular network remodeling. METHODS: Cultured adult Wistar rat mesenteric tissues were labeled with BSI-lectin and time-lapse images were captured over five days of serum-stimulated remodeling. Additionally, rat mesenteric tissues on day 0 and day 3 and 5 post-culture were labeled for PECAM + LYVE-1 or PECAM + podoplanin. RESULTS: Cultured networks were characterized by increases in blood capillary sprouting, lymphatic sprouting, and the number of lymphatic/blood vessel connections. Comparison of images from the same network regions identified incorporation of lymphatic vessels into blood vessels. Mosaic lymphatic/blood vessels contained lymphatic marker positive and negative endothelial cells. CONCLUSIONS: Our results reveal the ability for lymphatic vessels to transition into blood vessels in adult microvascular networks and discover a new paradigm for investigating lymphatic/blood endothelial cell dynamics during microvascular remodeling.

The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors.

The adhesion class of G protein-coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N-terminal region that is linked to a C-terminal seven transmembrane (7TM) domain via a GPCR-autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS). Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N-terminal fragment (NTF) bound to the 7TM of the C-terminal fragment (CTF). The NTFs of most aGPCRs contain domains known to be involved in cell-cell adhesion, while the CTFs are involved in classical G protein signaling, as well as other intracellular signaling. In this workshop report, we review the most recent findings on the biology, signaling mechanisms, and physiological functions of aGPCRs.

Remembering: Does the emotional content of a photograph affect boundary extension?

Observers falsely remember seeing beyond the bounds of a photograph (i.e., boundary extension [BE]). Do observers "zoom in" when viewing negative emotion photographs, resulting in boundary restriction (Safer, Christianson, Autry, & Österlund, 1998)? Studies have yielded inconsistent outcomes, perhaps because emotional valence was compared across photographs of completely different scenes. To control physical scene structure, two contrasting (negative vs. positive) emotional versions of the same scenes were created by dramatically changing individuals' facial expressions; 14 such scene pairs were selected based on participants' (n = 134) ratings of the emotional valence elicited. We attempted to enhance sensitivity to negative scene content by including participants who scored either high (n = 104) or low (n = 104) on trait rumination, which is characterized by repetitive analysis of negative mood and a narrowing of attention. They viewed either all negative or all positive emotion scenes (15 s each). These scenes were repeated at test and rated as "the same," "closer-up," or "farther away" than the stimulus view (on a 5-point scale). Participants in all groups exhibited BE, but neither emotional valence nor trait rumination affected performance, even though mood induction had occurred. Only physical scene context affected BE (irrespective of the emotional valence of the scenes). Results underscore the importance of controlling physical scene context in tests of the effect of emotion on spatial memory. The resilience of BE to negative-mood-inducing scenes is discussed in terms of the adaptive value of anticipating one's surroundings while navigating through scenes in the world. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cross-Jurisdictional Data Exchange Impact on the Estimation of the HIV Population Living in the District of Columbia: Evaluation Study.

BACKGROUND: Accurate HIV surveillance data are essential to monitor trends to help end the HIV epidemic. Owing to strict policies around data security and confidentiality, HIV surveillance data have not been routinely shared across jurisdictions except a biannual case-by-case review process to identify and remove duplicate cases (Routine Interstate Duplicate Review, RIDR). HIV surveillance estimates for the District of Columbia (DC) are complicated by migration and care seeking throughout the metropolitan area, which includes Maryland and Virginia. To address gaps in HIV surveillance data, health departments of DC, Maryland, and Virginia have established HIV surveillance data sharing agreements. Although the Black Box (a privacy data integration tool external to the health departments) facilitates the secure exchange of data between DC, Maryland, and Virginia, its previous iterations were limited by the frequency and scope of information exchanged. The health departments of DC, Maryland, and Virginia engaged in data sharing to further improve HIV surveillance estimates. OBJECTIVE: This study assessed the impact of cross-jurisdictional data sharing on the estimation of people living with HIV in DC and reduction of cases in the RIDR process. METHODS: Data sharing agreements established in 2014 allowed for the exchange of HIV case information (eg, current residential address) and laboratory information (eg, test types, result dates, and results) from the enhanced HIV/AIDS Reporting System (eHARS). Regular data exchanges began in 2017. The participating jurisdictions transferred data (via secure file transfer protocol) for individuals having a residential address in a partnering jurisdiction at the time of HIV diagnosis or evidence of receiving HIV-related services at a facility located in a partnering jurisdiction. The DC Department of Health compared the data received to DC eHARS and imported updated data that matched existing cases. Evaluation of changes in current residential address and HIV prevalence was conducted by comparing data before and after HIV surveillance data exchanges. RESULTS: After the HIV surveillance data exchange, an average of 396 fewer cases were estimated to be living in DC each year from 2012 to 2016. Among cases with a residential status change, 66.4% (1316/1982) had relocated to Maryland and 19.8% (392/1982) to Virginia; majority of these had relocated to counties bordering DC. Relocation in and out of DC differed by mode of transmission, race and ethnicity, age group, and gender. After data exchange, the volume of HIV cases needing RIDR decreased by 74% for DC-Maryland and 81% for DC-Virginia. CONCLUSIONS: HIV surveillance data exchange between the public health departments of DC, Maryland, and Virginia reduced the number of cases misclassified as DC residents and reduced the number of cases needing RIDR. Continued data exchanges will enhance the ability of DC Department of Health to monitor the local HIV epidemic.

Selective Role of RGS9-2 in Regulating Retrograde Synaptic Signaling of Indirect Pathway Medium Spiny Neurons in Dorsal Striatum.

In the striatum, medium spiny neurons (MSNs) are heavily involved in controlling movement and reward. MSNs form two distinct populations expressing either dopamine receptor 1 (D1-MSN) or dopamine receptor 2 (D2-MSN), which differ in their projection targets and neurochemical composition. The activity of both types of MSNs is shaped by multiple neuromodulatory inputs processed by GPCRs that fundamentally impact their synaptic properties biasing behavioral outcomes. How these GPCR signaling cascades are regulated and what downstream targets they recruit in D1-MSN and D2-MSN populations are incompletely understood. In this study, we examined the cellular and molecular mechanisms underlying the action of RGS9-2, a key GPCR regulator in MSNs implicated in both movement control and actions of addictive drugs. Imaging cultured striatal neurons, we found that ablation of RGS9-2 significantly reduced calcium influx through NMDARs. Electrophysiological recordings in slices confirmed inhibition of NMDAR function in MSNs, resulting in enhanced AMPAR/NMDAR ratio. Accordingly, male mice lacking RGS9-2 displayed behavioral hypersensitivity to NMDAR blockade by MK-801 or ketamine. Recordings from genetically identified populations of striatal neurons revealed that these changes were selective to D2-MSNs. Surprisingly, we found that these postsynaptic effects resulted in remodeling of presynaptic inputs to D2-MSNs increasing the frequency of mEPSC and inhibiting paired-pulse ratio. Pharmacological dissection revealed that these adaptations were mediated by the NMDAR-dependent inhibition of retrograde endocannabinoid signaling from D2-MSNs to CB1 receptor on presynaptic terminals. Together, these data demonstrate a novel mechanism for pathway selective regulation of synaptic plasticity in MSNs controlled by GPCR signaling.SIGNIFICANCE STATEMENT This study identifies a role for a major G-protein regulator in controlling synaptic properties of striatal neurons in a pathway selective fashion.

Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly.

Synapse assembly likely requires postsynaptic target recognition by incoming presynaptic afferents. Using newly generated conditional knock-in and knockout mice, we show in this study that latrophilin-2 (Lphn2), a cell-adhesion G protein-coupled receptor and presumptive α-latrotoxin receptor, controls the numbers of a specific subset of synapses in CA1-region hippocampal neurons, suggesting that Lphn2 acts as a synaptic target-recognition molecule. In cultured hippocampal neurons, Lphn2 maintained synapse numbers via a postsynaptic instead of a presynaptic mechanism, which was surprising given its presumptive role as an α-latrotoxin receptor. In CA1-region neurons in vivo, Lphn2 was specifically targeted to dendritic spines in the stratum lacunosum-moleculare, which form synapses with presynaptic entorhinal cortex afferents. In this study, postsynaptic deletion of Lphn2 selectively decreased spine numbers and impaired synaptic inputs from entorhinal but not Schaffer-collateral afferents. Behaviorally, loss of Lphn2 from the CA1 region increased spatial memory retention but decreased learning of sequential spatial memory tasks. Thus, Lphn2 appears to control synapse numbers in the entorhinal cortex/CA1 region circuit by acting as a domain-specific postsynaptic target-recognition molecule.

ß-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling.

α- and ß-neurexins are presynaptic cell-adhesion molecules implicated in autism and schizophrenia. We find that, although ß-neurexins are expressed at much lower levels than α-neurexins, conditional knockout of ß-neurexins with continued expression of α-neurexins dramatically decreased neurotransmitter release at excitatory synapses in cultured cortical neurons. The ß-neurexin knockout phenotype was attenuated by CB1-receptor inhibition, which blocks presynaptic endocannabinoid signaling, or by 2-arachidonoylglycerol synthesis inhibition, which impairs postsynaptic endocannabinoid release. In synapses formed by CA1-region pyramidal neurons onto burst-firing subiculum neurons, presynaptic in vivo knockout of ß-neurexins aggravated endocannabinoid-mediated inhibition of synaptic transmission and blocked LTP; presynaptic CB1-receptor antagonists or postsynaptic 2-arachidonoylglycerol synthesis inhibition again reversed this block. Moreover, conditional knockout of ß-neurexins in CA1-region neurons impaired contextual fear memories. Thus, our data suggest that presynaptic ß-neurexins control synaptic strength in excitatory synapses by regulating postsynaptic 2-arachidonoylglycerol synthesis, revealing an unexpected role for ß-neurexins in the endocannabinoid-dependent regulation of neural circuits.

Incentive salience: novel treatment strategies for major depression.

This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates "wanting," or anticipatory reward, rather than "liking," or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or "liking," it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.

Vertebral fractures in two alpaca crias with rickets syndrome.

CASE REPORT: Two dark-coloured alpaca crias aged 5 and 5.5 months, respectively, born in September in the Pacific Northwest, USA, were presented for evaluation of acute recumbency. Both crias had cervical spine fractures and one had additional fractures in other locations within the spine. Both crias had valgus deformities of the forelimbs and one had similar deformities of the hindlimbs. Both crias showed characteristic radiological signs of rickets syndrome, including wide, irregular physes, cupping of the metaphyses, bowing of long bones, pathological fractures and enlarged costochondral junctions. One cria responded clinically to treatment with parenteral administration of vitamin D. The other cria was euthanased because of the multiple spinal fractures and postmortem examination supported the diagnosis of rickets syndrome. CONCLUSIONS: Hypovitaminosis D is associated with abnormal bone formation in young growing animals. The clinical and laboratory findings of rickets syndrome in camelids in the Pacific Northwest, and other regions with low annual sunlight exposure, have been described, although there are only few reports of the radiological signs associated with this condition in camelids and other animals. Additionally, vertebral fractures have not been previously reported in animals with rickets syndrome. Because vertebral fractures were identified in both crias in this report, it suggests that this is a common and clinically important manifestation of the disease in alpaca crias. Hence, in geographic regions with low sunlight exposure, rickets syndrome should be considered as a differential diagnosis in crias presenting with clinical signs consistent with vertebral fracture.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.

OBJECTIVE: The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD: In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS: In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS: Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development.

Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.

Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity.

At hippocampal excitatory synapses, endocannabinoids (eCBs) mediate two forms of retrograde synaptic inhibition that are induced by postsynaptic depolarization or activation of metabotropic glutamate receptors (mGluRs). The homer family of molecular scaffolds provides spatial organization to regulate postsynaptic signaling cascades, including those activated by mGluRs. Expression of the homer 1a (H1a) immediate-early gene produces a short homer protein that lacks the domain required for homer oligomerization, enabling it to uncouple homer assemblies. Here, we report that H1a differentially modulates two forms of eCB-mediated synaptic plasticity, depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). EPSCs were recorded from cultured hippocampal neurons and DSE evoked by a 15 s depolarization to 0 mV and MSE evoked by a type I mGluR agonist. Expression of H1a enhanced DSE and inhibited MSE at the same synapse. Many physiologically important stimuli initiate H1a expression including brain-derived neurotrophic factor (BDNF). Treating hippocampal cultures with BDNF increased transcription of H1a and uncoupled homer 1c-GFP (green fluorescent protein) clusters. BDNF treatment blocked MSE and enhanced DSE. Thus, physiological changes in H1a expression gate the induction pathway for eCB-mediated synaptic plasticity by uncoupling mGluR from eCB production.

R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine.

In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gbeta5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gbeta5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum. In this study, we report that elimination of R7BP in mice results in motor coordination deficits and greater locomotor response to morphine administration, consistent with the essential role of R7BP in maintaining RGS9-2 expression in the striatum. However, in contrast to previously reported observations with RGS9-2 knockouts, mice lacking R7BP do not show higher sensitivity to locomotor-stimulating effects of cocaine. Using a striatum-specific knockdown approach, we show that the sensitivity of motor stimulation to cocaine is instead dependent on RGS7, whose complex formation with R7BP is dictated by RGS9-2 expression. These results indicate that dopamine signaling in the striatum is controlled by concerted interplay between two RGS proteins, RGS7 and RGS9-2, which are balanced by a common subunit, R7BP.