Hypertrophy and altered activity of the adrenal cortex in Homer 1 knockout mice.

Homer 1 gene products are involved in synaptic transmission and plasticity, and hence, distinct behavioral abnormalities, including anxiety- and depression-like behaviors, have been observed in Homer 1 knockout (KO) mice. Here we report that Homer 1 KO mice additionally exhibit a pronounced endocrine phenotype, displaying a profoundly increased adrenal gland weight and increased adrenal/body weight ratio. Histological examinations of Homer 1 deficient adrenal glands revealed an increased size of the adrenal cortex, especially the sizes of the zona fasciculata and zona glomerulosa. Moreover, the plasma corticosterone and aldosterone were higher in Homer 1 KO than wild-type (WT) mice while the plasma ACTH levels were not different between the genotypes. The in vivo ACTH test revealed that corticosterone and aldosterone plasma levels were higher in saline injected Homer 1 KO mice than in WT mice (saline injected mice served as controls for the respective groups of ACTH-injected animals), but the magnitude of steroid responses to ACTH was similar in both genotypes. In contrast, an in vitro experiment performed on isolated cells of adrenal cortex clearly showed increased production of both steroids in response to ACTH in Homer 1 KO cells, which is in line with an ~8-fold increase in the expression of ACTH receptor mRNA in the adrenal cortex of these mutants. These results, together with the detection of Homer 1 mRNA and protein in the adrenal cortex of WT mice, indicate that Homer 1 directly affects the steroidogenic function of the adrenal glands.

Complex, multimodal behavioral profile of the Homer1 knockout mouse.

Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wild-type (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia.

Homer proteins are involved in the functional assembly of postsynaptic density proteins at glutamatergic synapses and are implicated in learning, memory and drug addiction. Here, we report that Homer1-knockout (Homer1-KO) mice exhibit behavioral and neurochemical abnormalities that are consistent with the animal models of schizophrenia. Relative to wild-type mice, Homer1-KO mice exhibited deficits in radial arm maze performance, impaired prepulse inhibition, enhanced 'behavioral despair', increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior. No-net-flux in vivo microdialysis revealed a decrease in extracellular glutamate content in the nucleus accumbens and an increase in the prefrontal cortex. Moreover, in Homer1-KO mice, cocaine did not stimulate a rise in frontal cortex extracellular glutamate levels, suggesting hypofrontality. These behavioral and neurochemical data derived from Homer1 mutant mice are consistent with the recent association of schizophrenia with a single-nucleotide polymorphism in the Homer1 gene and suggest that the regulation of extracellular levels of glutamate within limbo-corticostriatal structures by Homer1 gene products may be involved in the pathogenesis of this neuropsychiatric disorder.

Interfering with chemokine networks--the hope for new therapeutics.

Chemokines are a large family of cytokines with a wide variety of biological actions. Originally, they were identified as controllers of the routine trafficking of immune cells, and directed migration of cells during inflammatory response - from which they get their name, a contraction of chemotactic cytokines. They are now also known to be active in angiogenesis, embryonic development and infection by viruses such as HIV-1. Studies with antibodies, modified chemokine and transgenic mice suggest that chemokine receptor antagonists may be selective anti-inflammatory, antiviral or immunomodulatory agents. Small-molecule antagonists of seven of the receptors have been reported, some with potency in the low nanomolar range. These compounds are shown to be active in cell biology assays; the next step will be to determine their efficacy in animal models of disease.

Homer 1 - a new player linking the hypothalamic-pituitary-adrenal axis activity to depression and anxiety.

Homer 1 gene products are involved in the regulation of synaptic transmission and plasticity. Beside other deficits, the Homer 1 knockout (KO) mice show distinct behavioural abnormalities, such as anxiety and depression-like behaviours. In addition, we recently reported that the global deletion of the Homer 1 proteins in mice leads to a conspicuous endocrine phenotype linked to hypertrophy of the adrenal cortex, elevated basal and/or adrenocorticotropic hormone-induced corticosterone and aldosterone release in vitro and in vivo, as well as a drastic increase in the adrenocorticotropic hormone receptor mRNA in the adrenocortical cells. Interestingly, the basal secretion of adrenocorticotropic hormone was not changed in these mutants, which is in line with our recent observations, suggesting that the central limb of the hypothalamic-pituitary-adrenal axis (namely hypothalamic corticotropin-releasing hormone levels and the activation of its neurons in response to restraint stress) is not affected in the Homer 1 KO mice. On the contrary, the elevation of both plasma and intra-adrenal corticosterone and aldosterone concentrations in these mutants clearly indicates that the alteration primarily occurred in the adrenal cortex. We propose that excessive steroid release may contribute to depression- and anxiety-like behaviours and that the Homer 1 gene products may be involved in the pathogenesis of these stress-related mood disorders.

Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels.

Homomeric glutamate receptor (GluR) channels become spontaneously active when the last alanine residue within the invariant SYTANLAAF-motif in the third membrane segment is substituted by threonine. The same mutation in the orphan GluRdelta2 channel is responsible for neurodegeneration in "Lurcher" (Lc) mice. Since most native GluRs are composed of different subunits, we investigated the effect of an Lc-mutated subunit in heteromeric kainate and AMPA receptors expressed in HEK293 cells. Kainate receptor KA2 subunits, either wild type or carrying the Lc mutation (KA2(Lc)), are retained inside the cell but are surface-expressed when assembled with GluR6 subunits. Importantly, KA2(Lc) dominates the gating of KA2(Lc)/GluR6(WT) channels, as revealed by spontaneous activation and by slowed desensitization and deactivation kinetics of ligand-activated whole-cell currents. Moreover, the AMPA receptor subunit GluR-B(Lc)(Q) which forms spontaneously active homomeric channels with rectifying current-voltage relationships, dominates the gating of heteromeric GluR-B(Lc)(Q)/GluR-A(R) channels. The spontaneous currents of these heteromeric AMPAR channels show linear current-voltage relationships, and the ligand-activated whole-cell currents display slower deactivation and desensitization kinetics than the respective wild-type channels. For heteromeric Lc-mutated kainate and AMPA receptors, the effects on kinetics were reduced relative to the homomeric Lc-mutated forms. Thus, an Lc-mutated subunit can potentially influence heteromeric channel function in vivo, and the severity of the phenotype will critically depend on the levels of homomeric GluR(Lc) and heteromeric GluR(Lc)/GluR(WT) channels.

Chemokine inhibition--why, when, where, which and how?

Chemokines are small chemoattractant cytokines that control a wide variety of biological and pathological processes, ranging from immunosurveillance to inflammation, and from viral infection to cancer. Genetic and pharmacological studies have shown that chemokines are responsible for the excessive recruitment of leucocytes to inflammatory sites and damaged tissue. In the present paper, we discuss the rationale behind interfering with the chemokine system and introduce various points for therapeutic intervention using either protein-based or small-molecule inhibitors. Unlike other cytokines, chemokines signal via seven-transmembrane GPCRs (G-protein-coupled receptors), which are favoured targets by the pharmaceutical industry, and, as such, they are the first cytokines for which small-molecule-receptor antagonists have been developed. In addition to the high-affinity receptor interaction, chemokines have an in vivo requirement to bind to GAGs (glycosaminoglycans) in order to mediate directional cell migration. Prevention of the GAG interaction has been shown to be a viable therapeutic strategy. Targeting chemokine intracellular signalling pathways offers an alternative small-molecule approach. One of the key signalling targets downstream of a variety of chemokine receptors identified to date is PI3Kgamma (phosphoinositide 3-kinase gamma), a member of the class I PI3K family. Thus the chemokine system offers many potential entry points for innovative anti-inflammatory therapies for autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and allergic contact dermatitis.