Author Correction: The emerging field of epigenetics in neurodegeneration and neuroprotection.

In Box 1 of this article, the positioning of the amino acid residues on the tail of histone H3 in part b of the figure was incorrect. These should have been oriented so that the K4 residue was the most distal labelled residue from the nucleosome core region. The corrected figure is shown below. The authors and editors thank T. Brown, R. Lober and C. Waker for bringing this error to our attention.

The emerging field of epigenetics in neurodegeneration and neuroprotection.

Epigenetic mechanisms - including DNA methylation, histone post-translational modifications and changes in nucleosome positioning - regulate gene expression, cellular differentiation and development in almost all tissues, including the brain. In adulthood, changes in the epigenome are crucial for higher cognitive functions such as learning and memory. Striking new evidence implicates the dysregulation of epigenetic mechanisms in neurodegenerative disorders and diseases. Although these disorders differ in their underlying causes and pathophysiologies, many involve the dysregulation of restrictive element 1-silencing transcription factor (REST), which acts via epigenetic mechanisms to regulate gene expression. Although not somatically heritable, epigenetic modifications in neurons are dynamic and reversible, which makes them good targets for therapeutic intervention.

Early uneven ear input induces long-lasting differences in left-right motor function.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.

Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice.

Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (Fmr1-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway. However, a role for autophagy in the pathophysiology of FXS is, as yet, unclear. Here we show that autophagic flux, a functional readout of autophagy, and biochemical markers of autophagy are down-regulated in hippocampal neurons of fragile X mice. We further show that enhanced activity of mammalian target of rapamycin complex 1 (mTORC1) and translocation of Raptor, a defining component of mTORC1, to the lysosome are causally related to reduced autophagy. Activation of autophagy by delivery of shRNA to Raptor directly into the CA1 of living mice via the lentivirus expression system largely corrects aberrant spine structure, synaptic plasticity, and cognition in fragile X mice. Postsynaptic density protein (PSD-95) and activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), proteins implicated in spine structure and synaptic plasticity, respectively, are elevated in neurons lacking fragile X mental retardation protein. Activation of autophagy corrects PSD-95 and Arc abundance, identifying a potential mechanism by which impaired autophagy is causally related to the fragile X phenotype and revealing a previously unappreciated role for autophagy in the synaptic and cognitive deficits associated with fragile X syndrome.

Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.

Translational control of mRNAs in dendrites is essential for certain forms of synaptic plasticity and learning and memory. CPEB is an RNA-binding protein that regulates local translation in dendrites. Here, we identify poly(A) polymerase Gld2, deadenylase PARN, and translation inhibitory factor neuroguidin (Ngd) as components of a dendritic CPEB-associated polyadenylation apparatus. Synaptic stimulation induces phosphorylation of CPEB, PARN expulsion from the ribonucleoprotein complex, and polyadenylation in dendrites. A screen for mRNAs whose polyadenylation is altered by Gld2 depletion identified >100 transcripts including one encoding NR2A, an NMDA receptor subunit. shRNA depletion studies demonstrate that Gld2 promotes and Ngd inhibits dendritic NR2A expression. Finally, shRNA-mediated depletion of Gld2 in vivo attenuates protein synthesis-dependent long-term potentiation (LTP) at hippocampal dentate gyrus synapses; conversely, Ngd depletion enhances LTP. These results identify a pivotal role for polyadenylation and the opposing effects of Gld2 and Ngd in hippocampal synaptic plasticity.

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.

Dysregulation of Mammalian Target of Rapamycin Signaling in Mouse Models of Autism.

The mammalian target of rapamycin (mTOR) is a central regulator of a diverse array of cellular processes, including cell growth, proliferation, autophagy, translation, and actin polymerization. Components of the mTOR cascade are present at synapses and influence synaptic plasticity and spine morphogenesis. A prevailing view is that the study of mTOR and its role in autism spectrum disorders (ASDs) will elucidate the molecular mechanisms by which mTOR regulates neuronal function under physiological and pathological conditions. Although many ASDs arise as a result of mutations in genes with multiple molecular functions, they appear to converge on common biological pathways that give rise to autism-relevant behaviors. Dysregulation of mTOR signaling has been identified as a phenotypic feature common to fragile X syndrome, tuberous sclerosis complex 1 and 2, neurofibromatosis 1, phosphatase and tensin homolog, and potentially Rett syndrome. Below are a summary of topics covered in a symposium that presents dysregulation of mTOR as a unifying theme in a subset of ASDs.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.

The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.

Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death.

Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown. Here, we show that REST is controlled at the level of protein stability via ß-TrCP-dependent, ubiquitin-based proteasomal degradation in differentiated neurons under physiological conditions and identify Casein Kinase 1 (CK1) as an upstream effector that bidirectionally regulates REST cellular abundance. CK1 associates with and phosphorylates REST at two neighboring, but distinct, motifs within the C terminus of REST critical for binding of ß-TrCP and targeting of REST for proteasomal degradation. We further show that global ischemia in rats in vivo triggers a decrease in CK1 and an increase in REST in selectively vulnerable hippocampal CA1 neurons. Administration of the CK1 activator pyrvinium pamoate by in vivo injection immediately after ischemia restores CK1 activity, suppresses REST expression, and rescues neurons destined to die. Our results identify a novel and previously unappreciated role for CK1 as a brake on REST stability and abundance in adult neurons and reveal that loss of CK1 is causally related to ischemia-induced neuronal death. These findings point to CK1 as a potential therapeutic target for the amelioration of hippocampal injury and cognitive deficits associated with global ischemia.

Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines.

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca(2+) permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca(2+) signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. Activation of ß-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca(2+) permeation, synaptic currents, and Ca(2+) rises in dendritic spines. We further show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca(2+) signaling at synapses and regulated by the emotional response to stress.

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death.

Dysregulation of the transcriptional repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor is important in a broad range of diseases, including cancer, diabetes, and heart disease. The role of REST-dependent epigenetic modifications in neurodegeneration is less clear. Here, we show that neuronal insults trigger activation of REST and CoREST in a clinically relevant model of ischemic stroke and that REST binds a subset of "transcriptionally responsive" genes (gria2, grin1, chrnb2, nefh, nfκb2, trpv1, chrm4, and syt6), of which the AMPA receptor subunit GluA2 is a top hit. Genes with enriched REST exhibited decreased mRNA and protein. We further show that REST assembles with CoREST, mSin3A, histone deacetylases 1 and 2, histone methyl-transferase G9a, and methyl CpG binding protein 2 at the promoters of target genes, where it orchestrates epigenetic remodeling and gene silencing. RNAi-mediated depletion of REST or administration of dominant-negative REST delivered directly into the hippocampus in vivo prevents epigenetic modifications, restores gene expression, and rescues hippocampal neurons. These findings document a causal role for REST-dependent epigenetic remodeling in the neurodegeneration associated with ischemic stroke and identify unique therapeutic targets for the amelioration of hippocampal injury and cognitive deficits.

Survivin Is a transcriptional target of STAT3 critical to estradiol neuroprotection in global ischemia.

Transient global ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons in humans and animals. It is well established that estrogens ameliorate neuronal death in animal models of focal and global ischemia. However, the role of signal transducer and activator of transcription-3 (STAT3) and its target genes in estradiol neuroprotection in global ischemia remains unclear. Here we show that a single intracerebral injection of 17ß-estradiol to ovariectomized female rats immediately after ischemia rescues CA1 neurons destined to die. Ischemia promotes activation of STAT3 signaling, association of STAT3 with the promoters of target genes, and STAT3-dependent mRNA and protein expression of prosurvival proteins in the selectively vulnerable CA1. In animals subjected to ischemia, acute postischemic estradiol further enhances activation and nuclear translocation of STAT3 and STAT3-dependent transcription of target genes. Importantly, we show that STAT3 is critical to estradiol neuroprotection, as evidenced by the ability of STAT3 inhibitor peptide and STAT3 shRNA delivered directly into the CA1 of living animals to abolish neuroprotection. In addition, we identify survivin, a member of the inhibitor-of-apoptosis family of proteins and known gene target of STAT3, as essential to estradiol neuroprotection, as evidenced by the ability of shRNA to survivin to reverse neuroprotection. These findings indicate that ischemia and estradiol act synergistically to promote activation of STAT3 and STAT3-dependent transcription of survivin in insulted CA1 neurons and identify STAT3 and survivin as potentially important therapeutic targets in an in vivo model of global ischemia.

Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity.

Autophagy is a conserved cellular mechanism that enables the degradation and recycling of cellular organelles and proteins via the lysosomal pathway. In neurodevelopment and maintenance of neuronal homeostasis, autophagy is required to regulate presynaptic functions, synapse remodeling, and synaptic plasticity. Deficiency of autophagy has been shown to underlie the synaptic and behavioral deficits of many neurological diseases such as autism, psychiatric diseases, and neurodegenerative disorders. Recent evidence reveals that dysregulated autophagy plays an important role in the initiation and progression of neuroinflammation, a common pathological feature in many neurological disorders leading to defective synaptic morphology and plasticity. In this review, we will discuss the regulation of autophagy and its effects on synapses and neuroinflammation, with emphasis on how autophagy is regulated by epigenetic mechanisms under healthy and diseased conditions.

Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses.

Group I metabotropic glutamate receptors (mGluR1/5) are important to synaptic circuitry formation during development and to forms of activity-dependent synaptic plasticity. Dysregulation of mGluR1/5 signaling is implicated in some disorders of neurodevelopment, including fragile X syndrome, the most common inherited form of intellectual disabilities and leading cause of autism. Site(s) in the intracellular loops of mGluR1/5 directly bind caveolin-1, an adaptor protein that associates with membrane rafts. Caveolin-1 is the main coat component of caveolae and organizes macromolecular signaling complexes with effector proteins and membrane receptors. We report that long-term depression (LTD) elicited by a single application of the group I mGluR selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was markedly attenuated at Schaffer collateral-CA1 synapses of mice lacking caveolin-1 (Cav1(-/-)), as assessed by field recording. In contrast, multiple applications of DHPG produced LTD comparable to that in WT mice. Passive membrane properties, basal glutamatergic transmission and NMDA receptor (NMDAR)-dependent LTD were unaltered. The remaining LTD was reduced by anisomycin, an inhibitor of protein synthesis, by U0126, an inhibitor of MEK1/2 kinases, and by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suggesting mediation by the same mechanisms as in WT. mGluR1/5-dependent activation (phosphorylation) of MEK and extracellular signal-regulated kinase (ERK1/2) was altered in Cav1(-/-) mice; basal phosphorylation was increased, but a single application of DHPG had no further effect, and after DHPG, phosphorylation was similar in WT and Cav1(-/-) mice. Taken together, our findings suggest that caveolin-1 is required for normal coupling of mGluR1/5 to downstream signaling cascades and induction of mGluR-LTD.

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia.

Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanism activated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1 expression requires PKA- and p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred, at least in part, via enhanced APE1 expression. Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a unique strategy for neuroprotection against hippocampal injury.

EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner.

Dynamic regulation of the localization and function of NMDA receptors (NMDARs) is critical for synaptic development and function. The composition and localization of NMDAR subunits at synapses are tightly regulated and can influence the ability of individual synapses to undergo long-lasting changes in response to stimuli. Here, we examine mechanisms by which EphB2, a receptor tyrosine kinase that binds and phosphorylates NMDARs, controls NMDAR subunit localization and function at synapses. We find that, in mature neurons, EphB2 expression levels regulate the amount of NMDARs at synapses, and EphB activation decreases Ca(2+)-dependent desensitization of NR2B-containing NMDARs. EphBs are required for enhanced localization of NR2B-containing NMDARs at synapses of mature neurons; triple EphB knock-out mice lacking EphB1-3 exhibit homeostatic upregulation of NMDAR surface expression and loss of proper targeting to synaptic sites. These findings demonstrate that, in the mature nervous system, EphBs are key regulators of the synaptic localization of NMDARs.

A silent synapse-based mechanism for cocaine-induced locomotor sensitization.

Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

Neuroprotective actions of estradiol and novel estrogen analogs in ischemia: translational implications.

This review highlights our investigations into the neuroprotective efficacy of estradiol and other estrogenic agents in a clinically relevant animal model of transient global ischemia, which causes selective, delayed death of hippocampal CA1 neurons and associated cognitive deficits. We find that estradiol rescues a significant number of CA1 pyramidal neurons that would otherwise die in response to global ischemia, and this is true when hormone is provided as a long-term pretreatment at physiological doses or as an acute treatment at the time of reperfusion. In addition to enhancing neuronal survival, both forms of estradiol treatment induce measurable cognitive benefit in young animals. Moreover, estradiol and estrogen analogs that do not bind classical nuclear estrogen receptors retain their neuroprotective efficacy in middle-aged females deprived of ovarian hormones for a prolonged duration (8weeks). Thus, non-feminizing estrogens may represent a new therapeutic approach for treating the neuronal damage associated with global ischemia.

CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X.

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca2+-permeable to GluA2-containing, Ca2+-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance-a common theme in FXS and other autism spectrum disorders.