A double pedigree reveals genetic but not cultural inheritance of cooperative personalities in wild banded mongooses.

Personality traits, such as the propensity to cooperate, are often inherited from parents to offspring, but the pathway of inheritance is unclear. Traits could be inherited via genetic or parental effects, or culturally via social learning from role models. However, these pathways are difficult to disentangle in natural systems as parents are usually the source of all of these effects. Here, we exploit natural 'cross fostering' in wild banded mongooses to investigate the inheritance of cooperative behaviour. Our analysis of 800 adult helpers over 21 years showed low but significant genetic heritability of cooperative personalities in males but not females. Cross fostering revealed little evidence of cultural heritability: offspring reared by particularly cooperative helpers did not become more cooperative themselves. Our results demonstrate that cooperative personalities are not always highly heritable in wild, and that the basis of behavioural traits can vary within a species (here, by sex).

Explaining negative kin discrimination in a cooperative mammal society.

Kin selection theory predicts that, where kin discrimination is possible, animals should typically act more favorably toward closer genetic relatives and direct aggression toward less closely related individuals. Contrary to this prediction, we present data from an 18-y study of wild banded mongooses, Mungos mungo, showing that females that are more closely related to dominant individuals are specifically targeted for forcible eviction from the group, often suffering severe injury, and sometimes death, as a result. This pattern cannot be explained by inbreeding avoidance or as a response to more intense local competition among kin. Instead, we use game theory to show that such negative kin discrimination can be explained by selection for unrelated targets to invest more effort in resisting eviction. Consistent with our model, negative kin discrimination is restricted to eviction attempts of older females capable of resistance; dominants exhibit no kin discrimination when attempting to evict younger females, nor do they discriminate between more closely or less closely related young when carrying out infanticidal attacks on vulnerable infants who cannot defend themselves. We suggest that in contexts where recipients of selfish acts are capable of resistance, the usual prediction of positive kin discrimination can be reversed. Kin selection theory, as an explanation for social behavior, can benefit from much greater exploration of sequential social interactions.

Control of Homeostatic Synaptic Plasticity by AKAP-Anchored Kinase and Phosphatase Regulation of Ca2+-Permeable AMPA Receptors.

Neuronal information processing requires multiple forms of synaptic plasticity mediated by NMDARs and AMPA-type glutamate receptors (AMPARs). These plasticity mechanisms include long-term potentiation (LTP) and long-term depression (LTD), which are Hebbian, homosynaptic mechanisms locally regulating synaptic strength of specific inputs, and homeostatic synaptic scaling, which is a heterosynaptic mechanism globally regulating synaptic strength across all inputs. In many cases, LTP and homeostatic scaling regulate AMPAR subunit composition to increase synaptic strength via incorporation of Ca2+-permeable receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits. Previous work by our group and others demonstrated that anchoring of the kinase PKA and the phosphatase calcineurin (CaN) to A-kinase anchoring protein (AKAP) 150 play opposing roles in regulation of GluA1 Ser845 phosphorylation and CP-AMPAR synaptic incorporation during hippocampal LTP and LTD. Here, using both male and female knock-in mice that are deficient in PKA or CaN anchoring, we show that AKAP150-anchored PKA and CaN also play novel roles in controlling CP-AMPAR synaptic incorporation during homeostatic plasticity in hippocampal neurons. We found that genetic disruption of AKAP-PKA anchoring prevented increases in Ser845 phosphorylation and CP-AMPAR synaptic recruitment during rapid homeostatic synaptic scaling-up induced by combined blockade of action potential firing and NMDAR activity. In contrast, genetic disruption of AKAP-CaN anchoring resulted in basal increases in Ser845 phosphorylation and CP-AMPAR synaptic activity that blocked subsequent scaling-up by preventing additional CP-AMPAR recruitment. Thus, the balanced, opposing phospho-regulation provided by AKAP-anchored PKA and CaN is essential for control of both Hebbian and homeostatic plasticity mechanisms that require CP-AMPARs.SIGNIFICANCE STATEMENT Neuronal circuit function is shaped by multiple forms of activity-dependent plasticity that control excitatory synaptic strength, including LTP/LTD that adjusts strength of individual synapses and homeostatic plasticity that adjusts overall strength of all synapses. Mechanisms controlling LTP/LTD and homeostatic plasticity were originally thought to be distinct; however, recent studies suggest that CP-AMPAR phosphorylation regulation is important during both LTP/LTD and homeostatic plasticity. Here we show that CP-AMPAR regulation by the kinase PKA and phosphatase CaN coanchored to the scaffold protein AKAP150, a mechanism previously implicated in LTP/LTD, is also crucial for controlling synaptic strength during homeostatic plasticity. These novel findings significantly expand our understanding of homeostatic plasticity mechanisms and further emphasize how intertwined they are with LTP and LTD.

GC-QTOFMS with a low-energy electron ionization source for advancing isotopologue analysis in 13C-based metabolic flux analysis.

For the study of different levels of (intra)cellular regulation and condition-dependent insight into metabolic activities, fluxomics experiments based on stable isotope tracer experiments using 13C have become a well-established approach. The experimentally obtained non-naturally distributed 13C labeling patterns of metabolite pools can be measured by mass spectrometric detection with front-end separation and can be consequently incorporated into biochemical network models. Here, despite a tedious derivatization step, gas chromatographic separation of polar metabolites is favorable because of the wide coverage range and high isomer separation efficiency. However, the typically employed electron ionization energy of 70 eV leads to significant fragmentation and consequently only low-abundant ions with an intact carbon backbone. Since these ions are considered a prerequisite for the analysis of the non-naturally distributed labeling patterns and further integration into modeling strategies, a softer ionization technique is needed. In the present work, a novel low energy electron ionization source is optimized for the analysis of primary metabolites and compared with a chemical ionization approach in terms of trueness, precision, and sensitivity.

The palmitoyl acyltransferase DHHC2 regulates recycling endosome exocytosis and synaptic potentiation through palmitoylation of AKAP79/150.

Phosphorylation and dephosphorylation of AMPA-type ionotropic glutamate receptors (AMPARs) by kinases and phosphatases and interactions with scaffold proteins play essential roles in regulating channel biophysical properties and trafficking events that control synaptic strength during NMDA receptor-dependent synaptic plasticity, such as LTP and LTD. We previously demonstrated that palmitoylation of the AMPAR-linked scaffold protein A-kinase anchoring protein (AKAP) 79/150 is required for its targeting to recycling endosomes in dendrites, where it regulates exocytosis from these compartments that is required for LTP-stimulated enlargement of postsynaptic dendritic spines, delivery of AMPARs to the plasma membrane, and maintenance of synaptic potentiation. Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms. In particular, RNAi-mediated knockdown of DHHC2 expression in rat hippocampal neurons disrupted stimulation of exocytosis from recycling endosomes, enlargement of dendritic spines, AKAP recruitment to spines, and potentiation of AMPAR-mediated synaptic currents that occur during LTP. Importantly, expression of a palmitoylation-independent lipidated AKAP mutant in DHHC2-deficient neurons largely restored normal plasticity regulation. Thus, we conclude that DHHC2-AKAP79/150 signaling is an essential regulator of dendritic recycling endosome exocytosis that controls both structural and functional plasticity at excitatory synapses.

Reproductive competition triggers mass eviction in cooperative banded mongooses.

In many vertebrate societies, forced eviction of group members is an important determinant of population structure, but little is known about what triggers eviction. Three main explanations are: (i) the reproductive competition hypothesis, (ii) the coercion of cooperation hypothesis, and (iii) the adaptive forced dispersal hypothesis. The last hypothesis proposes that dominant individuals use eviction as an adaptive strategy to propagate copies of their alleles through a highly structured population. We tested these hypotheses as explanations for eviction in cooperatively breeding banded mongooses (Mungos mungo), using a 16-year dataset on life history, behaviour and relatedness. In this species, groups of females, or mixed-sex groups, are periodically evicted en masse. Our evidence suggests that reproductive competition is the main ultimate trigger for eviction for both sexes. We find little evidence that mass eviction is used to coerce helping, or as a mechanism to force dispersal of relatives into the population. Eviction of females changes the landscape of reproductive competition for remaining males, which may explain why males are evicted alongside females. Our results show that the consequences of resolving within-group conflict resonate through groups and populations to affect population structure, with important implications for social evolution.

Banded mongooses avoid inbreeding when mating with members of the same natal group.

Inbreeding and inbreeding avoidance are key factors in the evolution of animal societies, influencing dispersal and reproductive strategies which can affect relatedness structure and helping behaviours. In cooperative breeding systems, individuals typically avoid inbreeding through reproductive restraint and/or dispersing to breed outside their natal group. However, where groups contain multiple potential mates of varying relatedness, strategies of kin recognition and mate choice may be favoured. Here, we investigate male mate choice and female control of paternity in the banded mongoose (Mungos mungo), a cooperatively breeding mammal where both sexes are often philopatric and mating between relatives is known to occur. We find evidence suggestive of inbreeding depression in banded mongooses, indicating a benefit to avoiding breeding with relatives. Successfully breeding pairs were less related than expected under random mating, which appeared to be driven by both male choice and female control of paternity. Male banded mongooses actively guard females to gain access to mating opportunities, and this guarding behaviour is preferentially directed towards less closely related females. Guard-female relatedness did not affect the guard's probability of gaining reproductive success. However, where mate-guards are unsuccessful, they lose paternity to males that are less related to the females than themselves. Together, our results suggest that both sexes of banded mongoose use kin discrimination to avoid inbreeding. Although this strategy appears to be rare among cooperative breeders, it may be more prominent in species where relatedness to potential mates is variable, and/or where opportunities for dispersal and mating outside of the group are limited.

Development of normal gestational ranges for the right myocardial performance index in the Australian population with three alternative caliper placements.

OBJECTIVES: To construct gestational age-adjusted reference ranges for the right fetal modified myocardial performance index (RMPI) in an Australian population and to assess the influence of valve click caliper position on constituent time intervals and the RMPI. METHODS: A prospective cross-sectional study of RMPI from 235 normal fetuses at 17-38 weeks of gestation was performed. Two Doppler waveforms were obtained: tricuspid and pulmonary valves for 'a' and 'b' readings, respectively. The ultrasound machine settings were: Doppler sweep velocity 15 cm/s, angle of insonation <15°, minimal gain, and wall motion filter 300 Hz. The 'a' and 'b' intervals were measured at three different caliper positions in each fetus: at the beginning of the original valve clicks ('original'), at the beginning of the reflected tricuspid and pulmonary closure clicks ('reflected') and at the peak of valve clicks ('peak'). RMPI was calculated as (a - b)/b. The three readings were obtained and averaged per examination, with intraobserver repeatability assessed by intraclass correlation coefficient (ICC) and 95% CI. RESULTS: For 'original', 'reflected' and 'peak' RMPI, mean ± SD, ICC (95% CI) were: 0.53 ± 0.10, 0.86 (0.83-0.89); 0.48 ± 0.10, 0.84 (0.81-0.87) and 0.48 ± 0.10, 0.89 (0.87-0.91), respectively. The RMPI increased by approximately 15% as gestation increased and decreased slightly with increasing heart rate. CONCLUSION: This is the first publication of reference ranges for RMPI based on caliper position. All methods showed good ICC, including the 'peak' method which we have previously proposed for routine use based on its repeatability and ease of identification when measuring the myocardial performance index.

Localised Objective Characterisation Assessment of Lymphoedema (LOCAL): Using High-Frequency Ultrasound, Bioelectrical Impedance Spectroscopy and Volume to Evaluate Superficial Tissue Composition.

Lymphoedema tissue is characterised by excess free fluid and structural changes to the extracellular matrix (ECM) in the form of fibrotic and fatty deposition. These tissue characteristics are integral to the assessment of lymphoedema progression; however, clinicians and researchers often focus on changes in the free fluid, volume and function of lymphatic vasculature to inform practice. Subsequently, little is known about the effect of clinical interventions on lymphoedema tissue composition. This article presents a novel approach to classify lymphoedema tissue. The Localised Objective Characterisation Assessment of Lymphoedema (LOCAL) classification combines diagnostic and clinically meaningful objective assessment thresholds to infer lymphoedema pathophysiological changes in tissue layers. The LOCAL classification method was verified using data from fifteen women with unilateral breast cancer-related lymphoedema who were evaluated at three sites on each arm using high-frequency ultrasound (HFUS), bio-electrical impedance spectroscopy (BIS) and volume measurements. Participants exhibited an uneven distribution of volume between the proximal and distal segments of the arm (p = 0.023), with multiple tissue compositional categories observed across sites on the same limb (p < 0.001). The LOCAL method demonstrated utility in categorising a diverse range of lymphoedema tissue layer changes beyond what can be ascertained from whole-limb measures.

Pitting Is Not Only a Measure of Oedema Presence: Using High-Frequency Ultrasound to Guide Pitting Test Standardisation for Assessment of Lymphoedema.

The pitting qualities of lymphoedema tissue change with disease progression. However, little is known about the underlying tissue response to the pitting test or the tissue characteristics that enhance or resist indentation. The pitting test is currently unstandardised, and the influence of test technique on pitting outcomes is unknown. Understanding how tissue reacts to applied pressure will build evidence for the standardisation of the pitting test. Ninety pitting test sites from fifteen women with unilateral breast cancer-related lymphoedema were evaluated using high-frequency ultrasound (HFUS), bioelectrical impedance spectroscopy (BIS), and limb volume measures. Three sites on each lymphoedema and non-lymphoedema arm were subject to a 60-s (s) staged pitting test, with changes in tissue features captured with ultrasound imaging before, throughout, and after the pitting test. Pitting qualities of tissues varied greatly, with lymphoedema sites pitting more frequently (p < 0.001) with greater depth (p < 0.001) and requiring a longer recovery time (p = 0.002) than contralateral unaffected tissue. Pitting is not solely attributable to oedema volume. Non-structural and structural characteristics of dermal and subcutaneous layers also influence tissue responses to sustained pressure. To enhance the validity and reliability of pitting assessment, a 60 s staged pitting test with an observation of tissue recovery is recommended for lymphoedema presentations.

AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula.

The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.

AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors.

AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1-GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca(2+) influx. However, a small number of Ca(2+)-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca(2+) signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca(2+)-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150ΔPIX knock-in mice to selectively disrupt CaN anchoring in vivo. We found that AKAP150ΔPIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150ΔPIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150ΔPIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca(2+)-permeable AMPARs both basally and during LTP and LTD.

Palmitoylation of A-kinase anchoring protein 79/150 regulates dendritic endosomal targeting and synaptic plasticity mechanisms.

NMDA receptor-dependent long-term potentiation (LTP) and depression (LTD) are forms of synaptic plasticity underlying learning and memory that are expressed through increases and decreases, respectively, in dendritic spine size and AMPA receptor (AMPAR) phosphorylation and postsynaptic localization. The A-kinase anchoring protein 79/150 (AKAP79/150) signaling scaffold regulates AMPAR phosphorylation, channel activity, and endosomal trafficking associated with LTP and LTD. AKAP79/150 is targeted to dendritic spine plasma membranes by an N-terminal polybasic domain that binds phosphoinositide lipids, F-actin, and cadherin cell adhesion molecules. However, we do not understand how regulation of AKAP targeting controls AMPAR endosomal trafficking. Here, we report that palmitoylation of the AKAP N-terminal polybasic domain targets it to postsynaptic lipid rafts and dendritic recycling endosomes. AKAP palmitoylation was regulated by seizure activity in vivo and LTP/LTD plasticity-inducing stimuli in cultured rat hippocampal neurons. With chemical LTP induction, we observed AKAP79 dendritic spine recruitment that required palmityolation and Rab11-regulated endosome recycling coincident with spine enlargement and AMPAR surface delivery. Importantly, a palmitoylation-deficient AKAP79 mutant impaired regulation of spine size, endosome recycling, AMPAR trafficking, and synaptic potentiation. These findings emphasize the emerging importance of palmitoylation in controlling synaptic function and reveal novel roles for the AKAP79/150 signaling complex in dendritic endosomes.

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3ß, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3ß activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3ß activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3ß. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 ( CDKL5 ) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3b, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3b activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3b activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3b. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces post-synaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated, key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity and human neuropathology.

Acoustic Radiation Force Impulse Elastography Assessment of Lymphoedema Tissue: An Insight into Tissue Stiffness.

Palpation remains essential for evaluating lymphoedema to detect subtle changes that may indicate progression. As palpation sense is not quantifiable, this study investigates the utility of ultrasound elastography to quantify stiffness of lymphoedema tissue and explore the influence of the pitting test on tissue stiffness. Fifteen women with unilateral arm lymphoedema were scanned using a Siemens S3000 Acuson ultrasound (Siemens, Germany) with 18 MHz and 9 MHz linear transducers to assess tissue structure and tissue stiffness with Acoustic Radiation Force Impulse elastography. Ninety sites were assessed, three on each of the lymphoedema-affected and contralateral unaffected arms. A subgroup of seven lymphoedema-affected sites included additional elastography imaging after a 60-s pitting test. Dermal tissue stiffness was greater than subcutaneous tissue stiffness regardless of the presence of pathology (p < 0.001). Lymphoedematous tissue exhibited a higher dermal to subcutaneous tissue stiffness ratio than contralateral sites (p = 0.005). Subgroup analysis indicated that the pitting test reduces dermal tissue stiffness (p = 0.018) and may alter the stiffness of the subcutaneous tissue layer. Elastography demonstrates potential as a complement to lymphoedema palpation assessment. The novel pre-test and post-pitting elastography imaging protocol yielded information representative of lymphoedema tissue characteristics that could not be ascertained from pre-test elastography images alone.

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome.

Genetic alterations in autism spectrum disorders (ASD) frequently disrupt balance between synaptic excitation and inhibition and alter plasticity in the hippocampal CA1 region. Individuals with Timothy Syndrome (TS), a genetic disorder caused by CaV1.2 L-type Ca2+ channel (LTCC) gain-of function mutations, such as G406R, exhibit social deficits, repetitive behaviors, and cognitive impairments characteristic of ASD that are phenocopied in TS2-neo mice expressing G406R. Here, we characterized hippocampal CA1 synaptic function in male TS2-neo mice and found basal excitatory transmission was slightly increased and inhibitory transmission strongly decreased. We also found distinct impacts on two LTCC-dependent forms of long-term potentiation (LTP) synaptic plasticity that were not readily consistent with LTCC gain-of-function. LTP induced by high-frequency stimulation (HFS) was strongly impaired in TS2-neo mice, suggesting decreased LTCC function. Yet, CaV1.2 expression, basal phosphorylation, and current density were similar for WT and TS2-neo. However, this HFS-LTP also required GABAA receptor activity, and thus may be impaired in TS2-neo due to decreased inhibitory transmission. In contrast, LTP induced in WT mice by prolonged theta-train (PTT) stimulation in the presence of a ß-adrenergic receptor agonist to increase CaV1.2 phosphorylation was partially induced in TS2-neo mice by PTT stimulation alone, consistent with increased LTCC function. Overall, our findings provide insights regarding how altered CaV1.2 channel function disrupts basal transmission and plasticity that could be relevant for neurobehavioral alterations in ASD.

ß-Amyloid disruption of LTP/LTD balance is mediated by AKAP150-anchored PKA and Calcineurin regulation of Ca2+-permeable AMPA receptors.

Regulated insertion and removal of postsynaptic AMPA glutamate receptors (AMPARs) mediates hippocampal long-term potentiation (LTP) and long-term depression (LTD) synaptic plasticity underlying learning and memory. In Alzheimer's disease ß-amyloid (Aß) oligomers may impair learning and memory by altering AMPAR trafficking and LTP/LTD balance. Importantly, Ca2+-permeable AMPARs (CP-AMPARs) assembled from GluA1 subunits are excluded from hippocampal synapses basally but can be recruited rapidly during LTP and LTD to modify synaptic strength and signaling. By employing mouse knockin mutations that disrupt anchoring of the kinase PKA or phosphatase Calcineurin (CaN) to the postsynaptic scaffold protein AKAP150, we find that local AKAP-PKA signaling is required for CP-AMPAR recruitment, which can facilitate LTP but also, paradoxically, prime synapses for Aß impairment of LTP mediated by local AKAP-CaN LTD signaling that promotes subsequent CP-AMPAR removal. These findings highlight the importance of PKA/CaN signaling balance and CP-AMPARs in normal plasticity and aberrant plasticity linked to disease.

Local miRNA-Dependent Translational Control of GABAAR Synthesis during Inhibitory Long-Term Potentiation.

Molecular mechanisms underlying plasticity at brain inhibitory synapses remain poorly characterized. Increased postsynaptic clustering of GABAA receptors (GABAARs) rapidly strengthens inhibition during inhibitory long-term potentiation (iLTP). However, it is unclear how synaptic GABAAR clustering is maintained to sustain iLTP. Here, we identify a role for miR376c in regulating the translation of mRNAs encoding the synaptic α1 and γ2 GABAAR subunits, GABRA1 and GABRG2, respectively. Following iLTP induction, transcriptional repression of miR376c is induced through a calcineurin-NFAT-HDAC signaling pathway and promotes increased translation and clustering of synaptic GABAARs. This pathway is essential for the long-term expression of iLTP and is blocked by miR376c overexpression, specifically impairing inhibitory synaptic strength. Finally, we show that local de novo synthesis of synaptic GABAARs occurs exclusively in dendrites and in a miR376c-dependent manner following iLTP. Together, this work describes a local post-transcriptional mechanism that regulates inhibitory synaptic plasticity via miRNA control of dendritic protein synthesis.