Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives.

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aß), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aß instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aß associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and ß-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Plasma ATN(I) classification and precision pharmacology in Alzheimer's disease.

Evaluating potential therapies for Alzheimer's disease (AD) depends on use of biomarkers for appropriate subject selection and monitoring disease progression. Biomarkers that predict onset of clinical symptoms are particularly important for AD because they enable intervention before irreversible neurodegeneration occurs. The amyloid-ß-tau-neurodegeneration (ATN) classification system is currently used as a biological staging model for AD and is based on three classes of biomarkers evaluating amyloid-ß (Aß), tau pathology and neurodegeneration or neuronal injury. Promising blood-based biomarkers for each of these categories have been identified (Aß42/Aß40 ratio, phosphorylated tau, neurofilament light chain), and this matrix is now being expanded toward an ATN(I) system, where "I" represents a neuroinflammatory biomarker. The plasma ATN(I) system, together with APOE genotyping, offers a basis for individualized evaluation and a move away from the classic "one size fits all" approach toward a biomarker-driven individualisation of therapy for patients with AD.

Role of ASIC1a in Normal and Pathological Synaptic Plasticity.

Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are broadly distributed in the mammalian nervous system where they play important roles in a variety of physiological processes, including neurotransmission and memory-related behaviors. In the last few years, we and others have investigated the role of ASIC1a in different forms of synaptic plasticity especially in the CA1 area of the hippocampus. This review summarizes the latest research linking ASIC1a to synaptic function either in physiological or pathological conditions. A better understanding of how these channels are regulated in brain circuitries relevant to synaptic plasticity and memory may offer novel targets for pharmacological intervention in neuropsychiatric and neurological disorders.

Pharmacological targeting of microglia dynamics in Alzheimer's disease: Preclinical and clinical evidence.

Numerous clinical trials of anti-amyloid agents for Alzheimer's disease (AD) were so far unsuccessful thereby challenging the validity of the amyloid hypothesis. This lack of progress has encouraged researchers to investigate alternative mechanisms in non-neuronal cells, among which microglia represent nowadays an attractive target. Microglia play a key role in the developing brain and contribute to synaptic remodeling in the mature brain. On the other hand, the intimate relationship between microglia and synapses led to the so-called synaptic stripping hypothesis, a process in which microglia selectively remove synapses from injured neurons. Synaptic stripping, along with the induction of a microglia-mediated chronic neuroinflammatory environment, promote the progressive synaptic degeneration in AD. Therefore, targeting microglia may pave the way for a new disease modifying approach. This review provides an overview of the pathophysiological roles of the microglia cells in AD and describes putative targets for pharmacological intervention. It also provides evidence for microglia-targeted strategies in preclinical AD studies and in early clinical trials.

Aducanumab for Alzheimer's disease: A regulatory perspective.

On June 7th 2021, the Food and Drug Administration (FDA) granted approval for Aduhelm (aducanumab) for the treatment of Alzheimer's disease under its accelerated approval program. Aducanumab is the first putative disease-modifying therapy (DMT) approved for the treatment of AD with a great potential for clinical benefit over current symptomatic therapies. The scientific community has been largely confounded by this historical decision since this has been based on the reduction of a surrogate marker (amyloid beta) and not on data showing clinical efficacy. Here we provide a regulatory perspective on the topic and discuss potential similarities and differences between the FDA's and EMA's evaluative processes.

Targeting Microglia-Synapse Interactions in Alzheimer's Disease.

In this review, we focus on the emerging roles of microglia in the brain, with particular attention to synaptic plasticity in health and disease. We present evidence that ramified microglia, classically believed to be "resting" (i.e., inactive), are instead strongly implicated in dynamic and plastic processes. Indeed, there is an intimate relationship between microglia and neurons at synapses which modulates activity-dependent functional and structural plasticity through the release of cytokines and growth factors. These roles are indispensable to brain development and cognitive function. Therefore, approaches aimed at maintaining the ramified state of microglia might be critical to ensure normal synaptic plasticity and cognition. On the other hand, inflammatory signals associated with Alzheimer's disease are able to modify the ramified morphology of microglia, thus leading to synapse loss and dysfunction, as well as cognitive impairment. In this context, we highlight microglial TREM2 and CSF1R as emerging targets for disease-modifying therapy in Alzheimer's disease (AD) and other neurodegenerative disorders.

Physical Exercise and Alzheimer's Disease: Effects on Pathophysiological Molecular Pathways of the Disease.

Alzheimer's disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.

Electroacupuncture in rats normalizes the diabetes-induced alterations in the septo-hippocampal cholinergic system.

Diabetes induces early sufferance in the cholinergic septo-hippocampal system, characterized by deficits in learning and memory, reduced hippocampal plasticity and abnormal pro-nerve growth factor (proNGF) release from hippocampal cells, all linked to dysfunctions in the muscarinic cholinergic modulation of hippocampal physiology. These alterations are associated with dysregulation of several cholinergic markers, such as the NGF receptor system and the acetylcholine biosynthetic enzyme choline-acetyl transferase (ChAT), in the medial septum and its target, the hippocampus. Controlled and repeated sensory stimulation by electroacupuncture has been proven effective in counteracting the consequences of diabetes on cholinergic system physiology in the brain. Here, we used a well-established Type 1 diabetes model, obtained by injecting young adult male rats with streptozotocin, to induce sufferance in the septo-hippocampal system. We then evaluated the effects of a 3-week treatment with low-frequency electroacupuncture on: (a) the expression and protein distribution of proNGF in the hippocampus, (b) the tissue distribution and content of NGF receptors in the medial septum, (c) the neuronal cholinergic and glial phenotype in the septo-hippocampal circuitry. Twice-a-week treatment with low-frequency electroacupuncture normalized, in both hippocampus and medial septum, the ratio between the neurotrophic NGF and its neurotoxic counterpart, the precursor proNGF. Electroacupuncture regulated the balance between the two major proNGF variants (proNGF-A and proNGF-B) at both gene expression and protein synthesis levels. In addition, electroacupuncture recovered to basal level the pro-neurotrophic NGF receptor tropomyosin receptor kinase-A content, down-regulated in medial septum cholinergic neurons by diabetes. Electroacupuncture also regulated ChAT content in medial septum neurons and its anterograde transport toward the hippocampus. Our data indicate that repeated sensory stimulation can positively affect brain circuits involved in learning and memory, reverting early impairment induced by diabetes development. Electroacupuncture could exert its effects on the septo-hippocampal cholinergic neurotransmission in diabetic rats, not only by rescuing the hippocampal muscarinic responsivity, as previously described, but also normalizing acetylcholine biosynthesis and NGF metabolism in the hippocampus.

Precision medicine and drug development in Alzheimer's disease: the importance of sexual dimorphism and patient stratification.

Neurodegenerative diseases (ND) are among the leading causes of disability and mortality. Considerable sex differences exist in the occurrence of the various manifestations leading to cognitive decline. Alzheimer's disease (AD) exhibits substantial sexual dimorphisms and disproportionately affects women. Women have a higher life expectancy compared to men and, consequently, have more lifespan to develop AD. The emerging precision medicine and pharmacology concepts - taking into account the individual genetic and biological variability relevant for disease risk, prevention, detection, diagnosis, and treatment - are expected to substantially enhance our knowledge and management of AD. Stratifying the affected individuals by sex and gender is an important basic step towards personalization of scientific research, drug development, and care. We hypothesize that sex and gender differences, extending from genetic to psychosocial domains, are highly relevant for the understanding of AD pathophysiology, and for the conceptualization of basic/translational research and for clinical therapy trial design.

The positive allosteric modulator at mGlu2 receptors, LY487379, reverses the effects of chronic stress-induced behavioral maladaptation and synaptic dysfunction in the adulthood.

Chronic stress induces maladaptive neural responses in several brain areas including hippocampus. It has been demonstrated that chronic stress exposure induced a downregulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors, which would reduce the negative feedback role exerted by these receptors. The reduced availability of these receptors would enhance glutamate overflow in the hippocampus, supporting the hypothesis that hippocampal glutamatergic neurotransmission plays a key etiopathological determinant in stress-induced neuropsychiatric disorders. Since modulation of glutamatergic neurotransmission has been shown to represent an interesting pharmacological tool to treat psychiatric disorders, in the present study we have investigated the effects of the mGlu2 receptor positive allosteric modulator (PAM) LY487379. The rational bases of our study were: (a) chronic restraint stress (CRS) application in C57/BALB6 mouse induced a loss of resilience at the behavioral, biochemical, and electrophysiological level; (b) a superimposed familiar stressor (restraint) but not unfamiliar (i.e., forced swim stress) completely reversed the effects of CRS. Using the CRS model, in the present study we have investigated the effects of LY487379, an mGlu2 PAM, as well as a superimposed familiar stressor (acute restraint stress-ARS), on the immobility time at the tail suspension test and electrophysiological profile of glutamatergic transmission in the dentate gyrus (DG).

PDGF Modulates Synaptic Excitability and Short-Latency Afferent Inhibition in Multiple Sclerosis.

Maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and PDGF plays a key role in this phenomenon. Indeed, higher cerebrospinal fluid PDGF concentration correlates with improved clinical recovery after a relapse, and the amplitude of LTP-like cortical plasticity in relapsing-remitting MS patients. However, LTP-like cortical plasticity varies depending on the individual level of inhibitory cortical circuits. Aim of this study was to explore whether PDGF-CSF concentration correlates with inhibitory cortical circuits explored by means of transcranial magnetic stimulation in patients affected by relapsing-remitting MS. We further performed electrophysiological experiments evaluating GABAergic transmission in the experimental autoimmune encephalomyelitis (EAE) hippocampus. Our results reveal that increased CSF PDGF concentration correlates with decreased short afferent inhibition in the motor cortex in MS patients and decreased GABAergic activity in EAE. These findings show that PDGF affects GABAergic activity both in MS patients and in EAE hippocampus.

Early alteration of distribution and activity of hippocampal type-1 cannabinoid receptor in Alzheimer's disease-like mice overexpressing the human mutant amyloid precursor protein.

Besides its involvement in Alzheimer's disease (AD) as precursor of the neurotoxic amyloid peptides, the pathophysiological impact of brain accumulation of amyloid precursor protein (APP) is not yet well understood. Recent studies reported that APP interacts with other membrane proteins, including G protein coupled receptors, affecting their biological functions. Here, we focused on the study of the potential impact of human mutant APP on expression, distribution and activity of type-1 cannabinoid (CB1) receptor in the hippocampus of Tg2576 mice, an AD-like mice model. By using biochemical and electrophysiological measures, we found that in a presymptomatic phase, when amyloid plaques have not yet formed and there is no sign of cognitive deficits, the over-expression of full-length APP in the hippocampus of Tg2576 mice altered membrane localization and inhibitory signalling activity of CB1 receptor, possibly by binding to the receptor and reducing its specific interaction with caveolin-1 and G proteins.

Neuregulin 1/ErbB signalling modulates hippocampal mGluRI-dependent LTD and object recognition memory.

The neurotrophic factors neuregulins (NRGs) and their receptors, ErbB tyrosine kinases, regulate neurotransmission, synaptic plasticity and cognitive functions and their alterations have been associated to different neuropsychiatric disorders. Group 1 metabotropic glutamate receptors (mGluRI)-dependent mechanisms are also altered in animal models of neuropsychiatric diseases, especially mGluRI-induced glutamatergic long-term depression (mGluRI-LTD), a form of synaptic plasticity critically involved in learning and memory. Despite this evidence, a potential link between NRGs/ErbB signalling and mGluRI-LTD has never been considered. Here, we aimed to test the hypothesis that NRGs/ErbB signalling regulates mGluRI functions in the hippocampus, thus controlling CA1 pyramidal neurons excitability and synaptic plasticity as well as mGluRI-dependent behaviors. We investigated the functional interaction between NRG1/ErbB signalling and mGluRI in hippocampal CA1 pyramidal neurons, by analyzing the effect of a pharmacological modulation of NRG1/ErbB signalling on the excitation of pyramidal neurons and on the LTD at CA3-CA1 synapses induced by an mGluRI agonist. Furthermore, we verified the involvement of ErbB signalling in mGluRI-dependent learning processes, by evaluating the consequence of an intrahippocampal in vivo injection of a pan-ErbB inhibitor in the object recognition test in mice, a learning task dependent on hippocampal mGluRI. We found that NRG1 potentiates mGluRI-dependent functions on pyramidal neurons excitability and synaptic plasticity at CA3-CA1 synapses. Further, endogenous ErbB signalling per se regulates, through mGluRI, neuronal excitability and LTD in CA1 pyramidal neurons, since ErbB inhibition reduces mGluRI-induced neuronal excitation and mGluRI-LTD. In vivo intrahippocampal injection of the ErbB inhibitor, PD158780, impairs mGluRI-LTD at CA3-CA1 synapses and affects the exploratory behavior in the object recognition test. Thus, our results identify a key role for NRG1/ErbB signalling in the regulation of hippocampal mGluRI-dependent synaptic and cognitive functions, whose alteration might contribute to the pathogenesis of different brain diseases.

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity.

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.

The role of adiponectin receptors in the regulation of synaptic transmission in the hippocampus.

In the last two decades adiponectin, member of the adipokines family, gained attention because of its unique antidiabetic effects. However, the presence in the brain of adiponectin receptors and adiponectin itself raised interest because of the possible association with neuropsychiatric diseases. Indeed, clinical studies found altered concentration of adiponectin both in plasma and cerebrospinal fluid in several pathologies including depression, multiple sclerosis, Alzheimer's disease and stroke. Moreover, recent preclinical studies also suggest its involvement in different physiological functions. Despite this evidence very few studies attempted to elucidate the functional role of adiponectin at the synapse. To address this question, here we investigated the effect of Adiporon, an agonist of both adiponectin receptors on synaptic transmission and LTP at Schaffer-collateral CA1 pathway. Surprisingly, increasing concentration of Adiporon correlated with lower CA1-LTP levels and paired-pulse ratio, whereas basal transmission was always preserved. Collectively, our data show that the adiponectin system, beyond its involvement in metabolic diseases, plays also a critical role in synaptic activity thereby representing a putative target for the treatment of synaptic pathologies.

Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism.

Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pahenu2 (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders.

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1-deficient mice.

Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease.

RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis.

BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1ß. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains.

Gender difference in prescription opioid abuse: A focus on oxycodone and hydrocodone.

Several data gathered in the last decade indicate an increase of abuse of prescription opioid drugs oxycodone (OXY) and hydrocodone (HYDRO) in women. However, to date there are no conclusive evidences investigating the gender-dependent abuse liability of prescription opioids. This study aims to supply a specific focus on women's data through a selective summary of the literature analyzing gender differences in the pharmacokinetic and pharmacodynamic dimension of OXY and HYDRO. Findings from this study suggest that the majority of OXY and HYDRO pharmacokinetic and pharmacodynamic effects do not differ according to gender, though confirming a significant difference in the incidence of adverse effects as demonstrated by the increased gastrointestinal adverse reactions in female subjects. Although the majority of recent clinical studies include an equal number of female and male subjects, the main outcome parameters do not relate specifically to gender differences. Due to the gender influence in activity of CYP3A4 and its crucial role in metabolism of both OXY than HYDRO, we suggest that assessing pharmacokinetic and pharmacodynamic interactions in clinical studies may be useful to clarify the effect of the higher CYP3A4 activity in female in relation to CYP2D6 genotype. Overall, considering the paucity of data regarding gender differences in European Union, this work highlights that impact of new abuse deterrent formulations should be assessed with a special focus on data concerning female subjects.

Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome.

Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.