Sexually dimorphic changes in the exploratory and habituation profiles of heterozygous neuregulin-1 knockout mice

Abstract

The neuregulin-1 gene is widely expressed in the central nervous system and is associated with increased risk for schizophrenia. Using an ethologically based approach, the phenotype of neuregulin-1 heterozygous knockout mice was examined by revealing the individual elements of behaviour in the murine repertoire over the prolonged course of interaction with the environment. During initial exploration, neuregulin-1 mutants displayed a phenotype characterized by increases in locomotion and rearing free, with sex-specific alterations in sifting and grooming. Over subsequent habituation, certain initial effects endured while new phenotypic effects emerged, some of which were again sex-specific. These studies elaborate a pleiotropic role of neuregulin-1 in development, plasticity and function, including sexual dimorphism, by defining the elemental, temporal and sex-specific characteristics of the neuregulin-1 mutant ethogram.

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…22 Finally, mouse models with disruptions in NRG1-ERBB4 signaling appear to capture some of the behavioral phenotypes associated with schizophrenia, and in certain cases these altered behaviors can be ameliorated by antipsychotics. 1,[23][24][25] Altogether, the data support a role for abnormal NRG1-ERB signaling in schizophrenia. Dissecting the pathways of NRG1-ERB signaling in the central nervous system may therefore contribute to the elucidation of pathways of schizophrenia susceptibility and may also reveal targets for interventions.…”

Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice

“…The value of an ethologically based approach to behavioural characterisation of mutant mice is increasingly recognised. It can identify novel phenotypic effects and resolve apparent inconsistencies in phenotype [4,7,22,23]. We have developed and applied such an approach to mice with knockout of each of the five DA receptor subtypes and components mediating DA receptor signal transduction [28].…”

“…Having applied this approach to NRG1 mutants [22,23], in the present study we examine in the same manner the functional role of the COMT gene. This allows us to address two critical questions.…”

Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling

“…As described previously (Nally et al, 2004;O'Sullivan et al, 2004O'Sullivan et al, , 2006O'Tuathaigh et al, 2006), for specification of the agonist-induced ethogram, the total 'counts' for each individual behavior were determined as the number of 5 s observation windows in which a given behavior was evident, summed over the 3 × 15 min [0 -15, 20 -35, 40 -55] cycle periods; data were expressed as means ± SEM. Stereotypy scores were averaged over the 60 min period and expressed similarly.…”

“…Mice were then allowed to habituate for a period of 3 h to reduce initially high levels of activity in order to optimise detection of agonist-induced stimulatory effects. Immediately following challenge with SKF 83822 (0.016 -2.0 mg/kg s.c.) or vehicle, assessments were carried out using a rapid time-sampling behavioral checklist technique and stereotypy rating scale, as previously described (Nally et al, 2004;c, 2006;O'Tuathaigh et al, 2006). For this study, the following components of the ethogram are reported: sniffing (flaring of nostrils with movement of vibrissae); locomotion (coordinated movement of all four limbs producing a change in location); rearing to wall (front paws reaching upwards onto or towards a cage wall while standing on hind limbs); total grooming (grooming of any form); intense grooming (characteristic, programmed syntax of sequential grooming of the snout and then the face with the forepaws, followed by grooming of the hind flank/anogenital region with the snout); seizures, characterised as any of the following phases occurring within the 60 min observation period: phase 1 = sustained immobility/rigidity; phase 2 = rearing with forepaw myoclonus; phase 3 = generalized clonus; phase 4 = tonic-clonic seizure or rapid jumping and wild running (Ferraro et al, 1999;McKhann et al, 2003;O'Sullivan et al, 2006); stillness (motionless: awake with no behavior evident, or asleep).…”