Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

Abstract

Rationale A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1+/−) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown. Objectives Mutant mice were assessed on electroencephalographic/event related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1+/−, Akt1−/− and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1+/− and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection. Results Akt1+/− and Akt1−/− mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired click stimulus, as well as reduced S1-S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1+/− mice displayed reduced pre-pulse inhibition. Conclusions Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.

Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population

“…Previous data from our group has suggested that the abnormalities in EEG and ERP observed in schizophrenia can be recreated by administration of NMDA receptor antagonists (Featherstone et al, 2012(Featherstone et al, , 2013Saunders et al, 2012a,b). For example, decreases in ERP amplitude are Fig.…”

“…The lack of effect on either S1 amplitude on its attenuation is consistent with the finding that disruptions in these measures are typically observed only following relatively high doses of NMDA antagonists (de Bruin et al, 1999;Lazarewicz et al, 2010;Oranje et al, 2002;Saunders et al, 2012b;van Berckel et al, 1998). In contrast to the effects of the obligatory ERP, many researchers have reported reliable and substantial effects of NMDA antagonists on baseline and event-related gamma power (Featherstone et al, 2013;Jones et al, 2012;Kittelberger et al, 2012;Lazarewicz et al, 2010;Pinault, 2008;Saunders et al, 2012a). Similarly, homozygous constitutive reduction of NR1 (NR1−/−) produces significant reduction in evoked activity (Bodarky et al, 2009;Gandal et al, 2012b;Halene et al, 2009).…”

Sensory encoding in Neuregulin 1 mutants

“…Describing the baseline activity in freely moving or anesthetized animals, studies found enhancements in oscillatory 30–80 Hz power (Carlen et al 2012; Del Pino et al 2013; Gandal et al 2012b; Hakami et al 2009; Kittelberger et al 2012; Kocsis 2012; Kulikova et al 2012; Ma and Leung 2007; Marquis et al 1989; Molina et al 2014; Pinault 2008) and in spiking activity (Belforte et al 2010; Carlen et al 2012; Jackson et al 2004; Molina et al 2014; Wood et al 2012; Zhang et al 2012) in different cortical and subcortical regions. In addition, reduced temporal precision of spiking and oscillatory activity has been reported in these models, in particular in the hippocampus and prefrontal cortex (Carlson et al 2011; Del Pino et al 2013; Featherstone et al 2013; Molina et al 2014; Nason et al 2011; Sigurdsson et al 2010; Zhang et al 2012). …”

“…In response to auditory stimulation under awake conditions, reduced oscillatory power has been described in various disease models (Carlson et al 2011; Featherstone et al 2013; Vohs et al 2012). However, an exact location of these deficits could not be defined due to the low spatial resolution of the EEG recordings.…”

Brown Norway rats, a putative schizophrenia model, show increased electroencephalographic activity at rest and decreased event-related potential amplitude, power, and coherence in the auditory sensory gating paradigm

“…Gandal et al (2012) demonstrated that NMDA-NR1 neo −/− mice, which have constitutively reduced expression of the NR1 subunit, showed deficits in the auditory-evoked signal-to-noise ratio. In addition, there are multiple reports that examine the neurophysiological deficits induced by pharmacological manipulation (Lazarewicz et al, 2010;Saunders et al, 2012;Featherstone et al, 2013). Taken together, these findings indicate that BN rats provide new opportunities for modeling schizophrenia in preclinical research field, however, the strengths and weakness of this model should be addressed in the future research by comparing the characteristics with other preclinical models such as optogenetic, single gene KO, and pharmacological models.…”