A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein-2 (MECP2), encoding a transcriptional regulator of many genes, including brain-derived neurotrophic factor (Bdnf). BDNF mRNA and protein levels are lower in RTT autopsy brains and in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of a brain penetrant, small molecule ligand of its TrkB receptors. Applied in vitro, LM22A-4 increased dendritic spine density in pyramidal neurons in cultured hippocampal slices from postnatal day (P) 7 male Mecp2 knockout (KO) mice as much as recombinant BDNF, and both effects were prevented by the TrkB receptor inhibitors K-252a and ANA-12. Consistent with its partial agonist activity, LM22A-4 did not affect spine density in CA1 pyramidal neurons in slice cultures from male wildtype (WT) mice, where typical BDNF levels outcompete its binding to TrkB. To identify neurons of known genotypes in the "mosaic" brain of female Mecp2 heterozygous (HET) mice, we treated 4-6-month-old female MeCP2-GFP WT and HET mice with peripheral injections of LM22A-4 for 4 weeks. Surprisingly, mutant neurons lacking MeCP2-GFP showed dendritic spine volumes comparable to that in WT controls, while MeCP2-GFP-expressing neurons showed larger spines, similar to the phenotype we described in symptomatic male Mecp2 KO mice where all neurons lack MeCP2. Consistent with this non-cell-autonomous mechanism, a 4-week systemic treatment with LM22A-4 had an effect only in MeCP2-GFP-expressing neurons in female Mecp2 HET mice, bringing dendritic spine volumes down to WT control levels, and without affecting spines of MeCP2-GFP-lacking neurons. At the behavioral level, we found that female Mecp2 HET mice engaged in aggressive behaviors significantly more than WT controls, which were reduced to WT levels by a 4-week systemic treatment with LM22A-4. Altogether, these data revealed differences in dendritic spine size and altered behaviors in Mecp2 HET mice, while providing support to the potential usefulness of BDNF-related therapeutic approaches such as the partial TrkB agonist LM22A-4.

Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses.

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIß. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIß phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that disruption of RIIß phosphorylation by Cdk5 enhances cortico-ventral striatal synaptic plasticity. In addition, we demonstrate that acute and chronic stress in rats inversely modulate RIIß phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIß regulation by Cdk5 improves behavioral response to stress. We propose this new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

Periodontal Infection Aggravates C1q-Mediated Microglial Activation and Synapse Pruning in Alzheimer's Mice.

Periodontitis is a dysbiotic infectious disease that leads to the destruction of tooth supporting tissues. There is increasing evidence that periodontitis may affect the development and severity of Alzheimer's disease (AD). However, the mechanism(s) by which periodontal infection impacts the neurodegenerative process in AD remains unclear. In the present study, using an amyloid precursor protein (APP) knock-in (App KI) AD mouse model, we showed that oral infection with Porphyromonas gingivalis (Pg), a keystone pathogen of periodontitis, worsened behavioral and cognitive impairment and accelerated amyloid beta (Aß) accumulation in AD mice, thus unquestionably and significantly aggravating AD. We also provide new evidence that the neuroinflammatory status established by AD, is greatly complicated by periodontal infection and the consequential entry of Pg into the brain via Aß-primed microglial activation, and that Pg-induced brain overactivation of complement C1q is critical for periodontitis-associated acceleration of AD progression by amplifying microglial activation, neuroinflammation, and tagging synapses for microglial engulfment. Our study renders support for the importance of periodontal infection in the innate immune regulation of AD and the possibility of targeting microbial etiology and periodontal treatment to ameliorate the clinical manifestation of AD and lower AD prevalence.

Identification of Socially-activated Neurons.

Determining the neuronal circuitry responsible for specific behaviors is a major focus in the field of neurobiology. Activity-dependent immediate early genes (IEGs), transcribed and translated shortly after neurons discharge action potentials, have been used extensively to either identify or gain genetic access to neurons and brain regions involved in such behaviors. By using immunohistochemistry for the protein product of the IEG c-Fos combined with retrograde labeling of specific neuronal populations, precise experimental timing, and identical data acquisition and processing, we present a method to quantitatively identify specific neuronal subpopulations that were active during social encounters. We have previously used this method to show a stronger recruitment of ventral hippocampal neurons that project to the medial prefrontal cortex, compared to those that project to the lateral hypothalamus, following social interactions. After optimization of surgeries for the injection of retrograde tracers, this method will be useful for the identification and mapping of neuronal populations engaged in many different behaviors.

Dysfunction of the corticostriatal pathway in autism spectrum disorders.

The corticostriatal pathway that carries sensory, motor, and limbic information to the striatum plays a critical role in motor control, action selection, and reward. Dysfunction of this pathway is associated with many neurological and psychiatric disorders. Corticostriatal synapses have unique features in their cortical origins and striatal targets. In this review, we first describe axonal growth and synaptogenesis in the corticostriatal pathway during development, and then summarize the current understanding of the molecular bases of synaptic transmission and plasticity at mature corticostriatal synapses. Genes associated with autism spectrum disorder (ASD) have been implicated in axonal growth abnormalities, imbalance of the synaptic excitation/inhibition ratio, and altered long-term synaptic plasticity in the corticostriatal pathway. Here, we review a number of ASD-associated high-confidence genes, including FMR1, KMT2A, GRIN2B, SCN2A, NLGN1, NLGN3, MET, CNTNAP2, FOXP2, TSHZ3, SHANK3, PTEN, CHD8, MECP2, DYRK1A, RELN, FOXP1, SYNGAP1, and NRXN, and discuss their relevance to proper corticostriatal function.

Differences in GluN2B-Containing NMDA Receptors Result in Distinct Long-Term Plasticity at Ipsilateral versus Contralateral Cortico-Striatal Synapses.

Excitatory neurons in the primary motor cortex project bilaterally to the striatum. However, whether synaptic structure and function in ipsilateral and contralateral cortico-striatal pathways is identical or different remains largely unknown. Here, we describe that excitatory synapses in the mouse contralateral pathway have higher levels of NMDA-type of glutamate receptors (NMDARs) than those in the ipsilateral pathway, although both synapses utilize the same presynaptic vesicular glutamate transporter (VGLUT). We also show that NMDARs containing the GluN2B subunit, but not GluN2A, contribute to this difference. The altered NMDAR subunit composition in these two pathways results in opposite synaptic plasticity induced by θ-burst stimulus: long-term depression in the ipsilateral pathway and long-term potentiation (LTP) in the contralateral pathway. The standard long-term depression (LTD)-inducing protocol using paired postsynaptic and presynaptic activity triggers synaptic depression at ipsilateral pathway synapses, but not at those of the contralateral pathway. Altogether, our results provide novel and unexpected evidence for the lack of bilaterality of NMDAR-mediated synaptic transmission at cortico-striatal pathways due to differences in the expression of GluN2B subunits, which results in differences in bidirectional synaptic plasticity.

The role of MeCP2 in learning and memory.

Gene transcription is a crucial step in the sequence of molecular, synaptic, cellular, and systems mechanisms underlying learning and memory. Here, we review the experimental evidence demonstrating that alterations in the levels and functionality of the methylated DNA-binding transcriptional regulator MeCP2 are implicated in the learning and memory deficits present in mouse models of Rett syndrome and MECP2 duplication syndrome. The significant impact that MeCP2 has on gene transcription through a variety of mechanisms, combined with well-defined models of learning and memory, make MeCP2 an excellent candidate to exemplify the role of gene transcription in learning and memory. Together, these studies have strengthened the concept that precise control of activity-dependent gene transcription is a fundamental mechanism that ensures long-term adaptive behaviors necessary for the survival of individuals interacting with their congeners in an ever-changing environment.

Ventral hippocampal projections to the medial prefrontal cortex regulate social memory.

Inputs from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC) are implicated in several neuropsychiatric disorders. Here, we show that the vHIP-mPFC projection is hyperactive in the Mecp2 knockout mouse model of the autism spectrum disorder Rett syndrome, which has deficits in social memory. Long-term excitation of mPFC-projecting vHIP neurons in wild-type mice impaired social memory, whereas their long-term inhibition in Rett mice rescued social memory deficits. The extent of social memory improvement was negatively correlated with vHIP-evoked responses in mPFC slices, on a mouse-per-mouse basis. Acute manipulations of the vHIP-mPFC projection affected social memory in a region and behavior selective manner, suggesting that proper vHIP-mPFC signaling is necessary to recall social memories. In addition, we identified an altered pattern of vHIP innervation of mPFC neurons, and increased synaptic strength of vHIP inputs onto layer five pyramidal neurons as contributing factors of aberrant vHIP-mPFC signaling in Rett mice.

Loss of Mecp2 Causes Atypical Synaptic and Molecular Plasticity of Parvalbumin-Expressing Interneurons Reflecting Rett Syndrome-Like Sensorimotor Defects.

Rett syndrome (RTT) is caused in most cases by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2). Understanding the pathological processes impacting sensory-motor control represents a major challenge for clinical management of individuals affected by RTT, but the underlying molecular and neuronal modifications remain unclear. We find that symptomatic male Mecp2 knockout (KO) mice show atypically elevated parvalbumin (PV) expression in both somatosensory (S1) and motor (M1) cortices together with excessive excitatory inputs converging onto PV-expressing interneurons (INs). In accordance, high-speed voltage-sensitive dye imaging shows reduced amplitude and spatial spread of synaptically induced neuronal depolarizations in S1 of Mecp2 KO mice. Moreover, motor learning-dependent changes of PV expression and structural synaptic plasticity typically occurring on PV+ INs in M1 are impaired in symptomatic Mecp2 KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female Mecp2 heterozygous mice. These results indicate that in Mecp2 mutant mice the configuration of PV+ INs network is shifted toward an atypical plasticity state in relevant cortical areas compatible with the sensory-motor dysfunctions characteristics of RTT.

Cdk5 Is Essential for Amphetamine to Increase Dendritic Spine Density in Hippocampal Pyramidal Neurons.

Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain. However, little is known about their effects in the hippocampus, where activity-dependent changes in the density of dendritic spine are associated with learning and memory. Recent reports suggest that Cdk5 plays an important role in drug addiction, but its role in psychostimulant's effects on dendritic spines in hippocampus remain unknown. We used in vivo and in vitro approaches to demonstrate that amphetamine increases dendritic spine density in pyramidal neurons of the hippocampus. Primary cultures and organotypic slice cultures were used for cellular, molecular, pharmacological and biochemical analyses of the role of Cdk5/p25 in amphetamine-induced dendritic spine formation. Amphetamine (two-injection protocol) increased dendritic spine density in hippocampal neurons of thy1-green fluorescent protein (GFP) mice, as well as in hippocampal cultured neurons and organotypic slice cultures. Either genetic or pharmacological inhibition of Cdk5 activity prevented the amphetamine-induced increase in dendritic spine density. Amphetamine also increased spine density in neurons overexpressing the strong Cdk5 activator p25. Finally, inhibition of calpain, the protease necessary for the conversion of p35 to p25, prevented amphetamine's effect on dendritic spine density. We demonstrate, for the first time, that amphetamine increases the density of dendritic spine in hippocampal pyramidal neurons in vivo and in vitro. Moreover, we show that the Cdk5/p25 signaling and calpain activity are both necessary for the effect of amphetamine on dendritic spine density. The identification of molecular mechanisms underlying psychostimulant effects provides novel and promising therapeutic approaches for the treatment of drug addiction.

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice.

Brain-derived neurotrophic factor (Bdnf) has been implicated in several neurological disorders including Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). The human BDNF gene has a single nucleotide polymorphism (SNP)-a methionine (met) substitution for valine (val) at codon 66-that affects BDNF's trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT) and Mecp2 knockout (KO) mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.

A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein-2 (MECP2), a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are reduced in RTT autopsy brains and in multiple brain areas of Mecp2-deficient mice. Furthermore, experimental interventions that increase BDNF levels improve RTT-like phenotypes in Mecp2 mutant mice. Here, we characterized the actions of a small-molecule ligand of the BDNF receptor TrkB in hippocampal function in Mecp2 mutant mice. Systemic treatment of female Mecp2 heterozygous (HET) mice with LM22A-4 for 4 weeks improved hippocampal-dependent object location memory and restored hippocampal long-term potentiation (LTP). Mechanistically, LM22A-4 acts to dampen hyperactive hippocampal network activity, reduce the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), and reduce the frequency of spontaneous tetrodotoxin-resistant Ca2+ signals in Mecp2 mutant hippocampal neurons, making them comparable to those features observed in wild-type neurons. Together, these observations indicate that LM22A-4 is a promising therapeutic candidate for the treatment of hippocampal dysfunction in RTT.

EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

KEY POINTS: Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. ABSTRACT: Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na+ channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons have lower levels of early endosome antigen 1 (EEA1), a protein involved in AMPA-type glutamate receptor endocytosis. In addition, expression of EEA1 in Mecp2 KO neurons reduced mEPSC amplitudes to wild-type levels, and restored synaptic scaling down of mEPSC amplitudes after 48 h blockade of GABAA R-mediated inhibition with bicuculline. The identification of a molecular deficit in HSP in Mecp2 KO neurons provides potentially novel targets of intervention for improving hippocampal function in Rett syndrome individuals.

The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin.

AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in the DTNBP1 gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse ortholog of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function.

Perineuronal Nets Suppress Plasticity of Excitatory Synapses on CA2 Pyramidal Neurons.

UNLABELLED: Long-term potentiation of excitatory synapses on pyramidal neurons in the stratum radiatum rarely occurs in hippocampal area CA2. Here, we present evidence that perineuronal nets (PNNs), a specialized extracellular matrix typically localized around inhibitory neurons, also surround mouse CA2 pyramidal neurons and envelop their excitatory synapses. CA2 pyramidal neurons express mRNA transcripts for the major PNN component aggrecan, identifying these neurons as a novel source for PNNs in the hippocampus. We also found that disruption of PNNs allows synaptic potentiation of normally plasticity-resistant excitatory CA2 synapses; thus, PNNs play a role in restricting synaptic plasticity in area CA2. Finally, we found that postnatal development of PNNs on CA2 pyramidal neurons is modified by early-life enrichment, suggesting that the development of circuits containing CA2 excitatory synapses are sensitive to manipulations of the rearing environment. SIGNIFICANCE STATEMENT: Perineuronal nets (PNNs) are thought to play a major role in restricting synaptic plasticity during postnatal development, and are altered in several models of neurodevelopmental disorders, such as schizophrenia and Rett syndrome. Although PNNs have been predominantly studied in association with inhibitory neurons throughout the brain, we describe a dense expression of PNNs around excitatory pyramidal neurons in hippocampal area CA2. We also provide insight into a previously unrecognized role for PNNs in restricting plasticity at excitatory synapses and raise the possibility of an early critical period of hippocampal plasticity that may ultimately reveal a key mechanism underlying learning and memory impairments of PNN-associated neurodevelopmental disorders.

Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.

Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.

Rett Syndrome: Reaching for Clinical Trials.

Rett syndrome (RTT) is a syndromic autism spectrum disorder caused by loss-of-function mutations in MECP2. The methyl CpG binding protein 2 binds methylcytosine and 5-hydroxymethycytosine at CpG sites in promoter regions of target genes, controlling their transcription by recruiting co-repressors and co-activators. Several preclinical studies in mouse models have identified rational molecular targets for drug therapies aimed at correcting the underlying neural dysfunction. These targeted therapies are increasingly translating into human clinical trials. In this review, we present an overview of RTT and describe the current state of preclinical studies in methyl CpG binding protein 2-based mouse models, as well as current clinical trials in individuals with RTT.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes.

Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.

Dendritic spine dysgenesis in autism related disorders.

The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target.