The stop null mice model for schizophrenia displays cognitive and social deficits partly alleviated by neuroleptics

Abstract

Recently evidence has accumulated that schizophrenia can arise from primary synaptic defects involving structural proteins particularly, microtubule associated proteins. Previous experiments have demonstrated that a STOP (stable tubule only peptide) gene deletion in mice leads to a phenotype mimicking some aspects of positive symptoms classically observed in schizophrenic patients. In the current study, we determined if STOP null mice demonstrate behavioral abnormalities related to the social and cognitive impairments of schizophrenia. Compared with wild-type mice, STOP null mice exhibited deficits in the non-aggressive component of social recognition, short term working memory and social and spatial learning. As described in humans, learning deficits in STOP null mice were poorly sensitive to long term treatment with typical neuroleptics. Since social and cognitive dysfunction have consistently been considered as central features of schizophrenia, we propose that STOP null mice may provide a useful model to understand the neurobiological correlates of social and cognitive defects in schizophrenia and to develop treatments that better target these symptoms.

Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice

“…Consistently with clinical data, long-term treatment with typical APs, such as haloperidol, has been shown to suppress hyperlocomotion disorders in STOP null mice (Brun et al 2005) as well as poorly effective on negative and cognitive defects (Bégou et al 2008). At the biological level, typical AP treatment has been shown to reverse shortterm plasticity defects and to be ineffective on long-term plasticity (Andrieux et al 2002).…”

“…Some of these locomotor activity defects are present in juvenile mice, whereas others appear only in adulthood mimicking thus the life-long evolution of the pathology (Begou et al 2007). Regarding negative or cognitive abilities, STOP null mice exhibit strong defects such as social withdrawal with dramatically reduced aggressive encounters (Andrieux et al 2002), deficits in prepulse inhibition (Andrieux et al 2002;Bouvrais-Veret et al 2007;Fradley et al 2005;Powell et al 2007), and recognition memory (Powell et al 2007), and spatial and social learning impairments (Bégou et al 2008). STOP null mice also exhibit hyperreactivity of dopamine release (Brun et al 2005) associated with a hypoglutamatergic phenotype (Andrieux et al 2002;Brenner et al 2007), in accordance with the dopamine/glutamate neurotransmission imbalance hypothesis in schizophrenia.…”

Deletion of CB2 Cannabinoid Receptor Induces Schizophrenia-Related Behaviors in Mice

“…The generation of mice with targeted mutation of these genes was focused on the development of genetic models of the putative regulation of the pathophysiological mechanisms (Gray et al, 2009;Halene et al, 2009;Han et al, 2009;Perry et al, 2009;Powell et al, 2008;Rojas et al, 2007;Sakae et al, 2008;Tanda et al, 2009;Wiedholz et al, 2008) and genetic models of risk for schizophrenia (Bégou et al, 2008;Dyck et al, 2009;Karl et al, 2007;Kvajo et al, 2008;Willi et al, 2010). Schizophrenia includes abnormalities in coordination and movement including extrapyramidal paradigms (tending toward higher motor activity) and catatonia (usually lower motor activity) (Peralta et al, 2010).…”

“…Using the step down inhibitory avoidance task, CB 2 KO mice showed disrupted short-and long-term memory consolidation of the task. Other genetically modified mice, proposed as animal models of behavioral and biochemical alterations implicated in schizophrenia, show deficits in short-term working and spatial memory (Bégou et al, 2008;Gray et al, 2009) and deficits in retention of emotional or spatial memory (Rojas et al, 2007;Tanda et al, 2009). However, not all these mutant mice present memory impairment; for instance, trace amine 1 receptor KO mice show no difference on a working memory task compared with WT mice (Wolinsky et al, 2007).…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…These alterations recapitulate some clinical features observed in schizophrenia disorders (Andrieux et al 2002;Fournet et al 2012b). Interestingly, chronic treatments with both typical and atypical antipsychotics improve some defects in MAP6 knockout mice (Andrieux et al 2002;Begou et al 2008;Brun et al 2005;Delotterie et al 2010;Fradley et al 2005;Merenlender-Wagner et al 2010). In addition, treatments with MT-stabilizing compounds like epothilone D and NAP (davunetide) also improved some of the deficits (Andrieux et al 2006;Fournet et al 2012a;MerenlenderWagner et al 2010).…”