Abnormal Behavior In Mice Research Articles

The Selective Metabotropic Glutamate 2/3 Receptor Agonist MGS0028 Reverses Isolation Rearing–Induced Abnormal Behaviors in Mice

Isolation-induced abnormal behaviors are useful animal models for assessing potential anti-psychotic drugs. This study examined the effect of MGS0028, a selective metabotropic glutamate 2/3 receptor agonist, on abnormal behaviors such as hyperactivity, aggression, and deficits of prepulse inhibition in isolation-reared mice. MGS0028 attenuated hyperactivity and aggressive behaviors in isolation-reared mice. The agonist also reversed isolation rearing–induced deficits of prepulse inhibition. On the other hand, MGS0028 did not affect locomotor activity and prepulse inhibition in group-reared mice. These results suggest that the metabotropic glutamate 2/3 receptor agonist, MGS0028, is a potential compound for the treatment of psychiatric disorders.

Abnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1

Disrupted-in-Schizophrenia-1 (DISC1) is a genetic susceptibility locus for major mental illness, including schizophrenia and depression. The Disc1 protein was recently shown to interact with the Wnt signaling protein, DIX domain containing 1 (Dixdc1). Both proteins participate in neural progenitor proliferation dependent on Wnt signaling, and in neural migration independently of Wnt signaling. Interestingly, their effect on neural progenitor proliferation is additive. By analogy to Disc1, mutations in Dixdc1 may lead to abnormal behavior in mice, and to schizophrenia or depression in humans. To explore this hypothesis further, we generated mice mutant at the Dixdc1 locus and analyzed their behavior. Dixdc1−/− mice had normal prepulse inhibition, but displayed decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity. Our results suggest that Dixdc1−/− mice will be a useful tool to elucidate molecular pathophysiology involving Disc1 in major mental illnesses.

Effects of repeated electroconvulsive shock on methamphetamine-induced behavioral abnormalities in mice

Methamphetamine abuse and addiction can lead to impaired cognition and psychosis, and there is no effective treatment for methamphetamine-induced mental illnesses. The aim of this study was to test whether repeated electroconvulsive shock (ECS) treatment has a therapeutic effect on methamphetamine-induced abnormal behavior in mice. To test the effects of ECS on methamphetamine-induced psychosis, ICR mice were randomly assigned to administration with either chronic methamphetamine or saline injection, and then both groups underwent post-treatment with either six once-daily ECS treatments or parallel sham controls. Prepulse inhibition (PPI), the novel object recognition test (NORT) and behavioral sensitization were performed for behavioral evaluation between the groups. To test the effects of ECS on methamphetamine addiction, methamphetamine-induced conditioned place preference (CPP) was examined after ECS and drug-primed reinstatement in the other set of experiments. The animals receiving repeated ECS following pretreatment with methamphetamine showed significant improvement in PPI and NORT, but not in behavioral sensitization. In the CPP study, the ECS-treated animals achieved extinction of place preference, but relapsed after a low-dose reinstatement of methamphetamine. The results indicated that repeated ECS treatments can ameliorate impairment to the sensorimotor gating and recognition memory elicited by methamphetamine, and temporarily suppress the reinforcement induced by methamphetamine in mice. Our findings suggest electroconvulsive therapy (ECT) may have potential applications with regard to the treatment of methamphetamine psychosis and addiction.

Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3

SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3(e4-9) homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3(e4-9) male mice display more severe impairments than females in motor coordination. Shank3(e4-9) mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3(e4-9) mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.

Effects of Gastrodia Elata Bl on Phencyclidine-Induced Schizophrenia-Like Psychosis in Mice

It has been demonstrated that 5-HT1A receptors play an important role in the pathophysiology of schizophrenia. Because Gastrodia elata Bl (GE) modulates the serotonergic system, we examined whether GE could affect phencyclidine (PCP)-induced abnormal behavior in mice. Repeated treatment with PCP increased immobility time, while it decreased social interaction time and recognition memory. PCP-induced abnormal behaviors were significantly attenuated by GE, and these effects were comparable to those of 8-OH-DPAT, a 5-HT1A receptor agonist. Furthermore, GE-mediated effects were counteracted by WAY 100635, a 5-HT1A receptor antagonist. Our results suggest that the antipsychotic effects of GE are, at least in part, mediated via activation of 5-HT1A in mice.

Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3

Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3

Targeted mutations in the Na,K‐ATPase alpha 2 isoform confer ouabain resistance and result in abnormal behavior in mice

Sodium and potassium-activated adenosine triphosphatases (Na,K-ATPase) are ubiquitous, participate in osmotic balance and membrane potential, and are composed of α, β, and γ subunits. The α subunit is required for the catalytic and transport properties of the enzyme and contains binding sites for cations, ATP, and digitalis-like compounds including ouabain. There are four known α isoforms; three that are expressed in the CNS in a regional and cell-specific manner. The α2 isoform is most commonly found in astrocytes, pyramidal cells of the hippocampus in adults, and developmentally in several other neuronal types. Ouabain-like compounds are thought to be produced endogenously in mammals, bind the Na,K-ATPase, and function as a stress-related hormone, however, the impact of the Na,K-ATPase ouabain binding site on neurobehavioral function is largely unknown. To determine if the ouabain binding site of the α2 isoform plays a physiological role in CNS function, we examined knock-in mice in which the normally ouabain-sensitive α2 isoform was made resistant (α2(R/R) ) while still retaining basal Na,K-ATPase enzymatic function. Egocentric learning (Cincinnati water maze) was impaired in adult α2(R/R) mice compared to wild type (WT) mice. They also exhibited decreased locomotor activity in a novel environment and increased responsiveness to a challenge with an indirect sympathomimetic agonist (methamphetamine) relative to WT mice. The α2(R/R) mice also demonstrated a blunted acoustic startle reflex and a failure to habituate to repeated acoustic stimuli. The α2(R/R) mice showed no evidence of altered anxiety (elevated zero maze) nor were they impaired in spatial learning or memory in the Morris water maze and neither group could learn in a large Morris maze. These results suggest that the ouabain binding site is involved in specific types of learning and the modulation of dopamine-mediated locomotor behavior.

Huntingtin-associated Protein-1 Deficiency in Orexin-producing Neurons Impairs Neuronal Process Extension and Leads to Abnormal Behavior in Mice

Huntingtin-associated protein-1 (Hap1) is a neuronal protein that associates with huntingtin, the Huntington disease protein. Although Hap1 and huntingtin are known to be involved in intracellular trafficking, whether and how the impairment of Hap1-associated trafficking leads to neurological pathology and symptoms remain to be seen. As Hap1 is enriched in neuronal cells in the brain, addressing this issue is important in defining the role of defective intracellular trafficking in the selective neuropathology associated with Hap1 dysfunction. Here, we find that Hap1 is abundantly expressed in orexin (hypocretin)-producing neurons (orexin neurons), which are distinctly distributed in the hypothalamus and play an important role in the regulation of feeding and behavior. We created conditional Hap1 knock-out mice to selectively deplete Hap1 in orexin neurons via the Cre-loxP system. These mice show process fragmentation of orexin neurons and reductions in food intake, body weight, and locomotor activity. Sucrose density gradient fractionation reveals that loss of Hap1 in the mouse brain also reduces the distribution of trafficking protein complexes and cargo proteins in the fractions that are enriched in synaptosomes. These results suggest that Hap1 is critical for the transport of multiple proteins to the nerve terminals to maintain the integrity of neuronal processes and that selective disruption of the processes of orexin neurons can cause abnormal feeding and locomotor activity.

Parishin C Attenuates Phencyclidine-Induced Schizophrenia-Like Psychosis in Mice: Involvements of 5-HT1A Receptor

Parishin C, a major component of Gastrodia elata BLUME (GE), was purified from GE. Because GE modulates the serotonergic system and the 5-HT1A receptor is an important therapeutic target of schizophrenia, we examined whether parishin C affects phencyclidine-induced abnormal behaviors in mice. Phencyclidine-induced abnormal behaviors were significantly ameliorated by parishin C. These effects were reversed by WAY 100635, a 5-HT1A–receptor antagonist. Consistently, parishin C showed high affinity at 5-HT1A receptor as well as a 5-HT1A–agonist activity in a 8-OH-DPAT–stimulated [ 35S]GTP-γS binding assay. Our results suggest that the antipsychotic effects of parishin C require activation of 5-HT1A receptors.

Vomeronasal organ ablation elicits chemosensory dysfunction and abnormal behavior in mice

This study aimed to examine whether the vomeronasal organ (VNO) is a prerequisite in mice to acquire essential information from various social odors and whether long-term VNO dysfunction can elicit behavioral and physiological changes in mice. We used binary choice tests and habituation–dishabituation tests to measure the abilities of male mice to recognize social odors. We found that males with the VNO ablation failed to show olfactory preferences between the odors of mate versus non-mate females, offspring versus non-offspring pups, or opposite-sex conspecifics versus predators (cats or rats), but were capable of discriminating between the two treatments in each of the paired odors, suggesting that male mice with VNO ablation might smell out the chemical differences of the two types of odors, but could not extract the biological information contained in the odors. Furthermore, prolonged VNO deficiency resulted in a reduction in crossing behavior in a light/dark box, the frequency of urine marking, and the time spent in the center in an open field. These results indicate that chronic VNO dysfunction led to anxiety-like or submissive behavior. In addition, males with VNO ablation had atrophic adrenal glands and hypertrophic preputial glands, suggesting that VNO dysfunction could damage the physiological conditions to buffer the stress and that pheromone perception deficiency might enhance self-odor production in mice.

Inhibition of calcineurin by infusion of CsA causes hyperphosphorylation of tau and is accompanied by abnormal behavior in mice

Calcineurin is a Ca2+/calmodulin-dependent phosphatase that dephosphorylates numerous substrates in different neuronal compartments. Genetic and pharmacological studies have provided insight into its involvement in the brain. Cyclosporin A (CsA) is used as a specific calcineurin inhibitor in many pharmacological experiments. However, the calcineurin activity of CsA-treated brain has not been reported. To examine the relationship between calcineurin activity and brain function, we injected CsA into the left lateral ventricle of the mouse brain and assayed calcineurin activity. CsA reduced calcineurin activity in a dose-dependent manner, without affecting the amount of calcineurin protein. Assays of the effect of protein phosphatase inhibitors on CsA-injected mouse brain extracts and kinetic analysis revealed that CsA inhibited calcineurin activity in a non-competitive manner in vivo, in agreement with in vitro results. Injection of CsA led to enhanced phosphorylation of tau at Ser-262 (12E8 site), Ser-198, Ser-199, and/or Ser-202 (Tau-1 site) and Ser-396 and/or Ser-404 (PHF-1 site), as well as to impaired spatial memory, which are two characteristic features of Alzheimer's disease. We propose that inhibition of calcineurin may play an important role in Alzheimer's disease.