Cognitive ﬂexibility in mice CONCLUDING REMARKS The Brigman et al. data raise some interest- ing questions for further studies examining the effects of subchronic PCP on reversal in the touchscreen system. For example, would increasing the difficulty of the reversal (e.g., by increasing the perceptual similarity of the visual stimuli), presenting distracters, or mak- ing reinforcement probabilistic, increase the sensitivity of the assay to PCP treatment? Such task-dependent effects would be intriguing, given the aforementioned clinical data hint- ing that the range of executive deficits may increase in tandem with disease chronicity and severity. In this context, another inter- esting course would be to parametrically vary dose and/or chronicity of treatment to ask whether more “intensive” treatment regimens produced significant reversal defi- cits. Beyond the subchronic PCP model, the touchscreen-based system has great potential for evaluating mouse models of schizophrenia Table 2 | Examples of studies of cognitive ﬂexibility in mutant mice. Assay Mutant Reversal effect Reference IDS/EDS IDS/EDS IDS/EDS IDS/EDS IDS/EDS MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM MWM Operant Operant Olfactory Olfactory Olfactory Spatial Spatial Spatial Spatial Spatial Spatial Spatial Spatial HdhCAC(150) knock-in Dopamine D2 receptor knockout Dopamine D3 receptor knockout COMT-Val transgenic Tg2576 APP Swedish mutation p25 fragment accumulation Vesicular glutamate transporter deﬁcient N-terminal amidase deﬁcient Ins2C96Y Akita Rac3 knockout TgCRND8 APP double mutant Synaptic vesicle protein (Rab3a) deﬁcient NaSi-1 sulfate transporter deﬁcient PDE1B−/− DARPP32−/− double knockout CREBcomp mutant mGluR4 deﬁcient α3-GABAa deﬁcient PS1 transgenic, L235P mutation β-amyloid precursor protein transgenic D-amino acid oxidase deﬁcient Presenilin 1 knockout Protein tyrosine phosphatase-alpha deﬁcient Offspring of vasoactive intestinal peptide deﬁcient dams Guanine nucleotide exchange factor (Ric-8) deﬁcient CB1 endocannabinoid receptor deﬁcient GDNF receptor α2 deﬁcient Heterozygous Reln deﬁcient “Reeler Mouse” Heterozygous Reln deﬁcient “Reeler Mouse” TgS and TgR acetylcholinesterase disruption Dopamine D2 receptor knockout Phenylalanine hydroxylase deﬁcient AMPA receptor subunit (GluRA) knockout Brain and spinal cord myelin deﬁcient APP/PS1 transgenic Ts65Dn cholinergic deﬁcient Down’s model DARPP-32 knockout PEPCK bGH transgenic elevated growth hormone APP/PS1 transgenic Alzheimer’s model AMPA receptor subunit (GluRA) knockout Impaired Impaired Facilitated None Impaired Facilitated Impaired Facilitated None Impaired Impaired Impaired None Impaired Impaired Facilitated Trend for impaired None Impaired Facilitated Rescues APP transgenic None Impaired Impaired Impaired Impaired Impaired None None Impaired Impaired Impaired Impaired Age-related impairment Impaired Impaired Facilitated None Impaired Brooks et al. (2006) De Steno and Schmauss (2009) Glickstein et al. (2005) Papaleo et al. (2008) Zhuo et al. (2007) Angelo et al. (2003) Balschun et al. (2009) Balogh et al. (2001) Choeiri et al. (2005) Corbetta et al. (2008) Chishti et al. (2001) D’Adamo et al. (2004) Dawson et al. (2005) Ehrman et al. (2006) Gass et al. (1998) Gerlai et al. (1998) Fiorelli et al. (2008) Huang et al. (2003) Koistinaho et al. (2001) Labrie et al. (2009) Saura et al. (2005) Skelton et al. (2003) Stack et al. (2008) Tonissoo et al. (2006) Varvel and Lichtman (2002) Voikar et al. (2004) Brigman et al. (2006) Krueger et al. (2006) Kofman et al. (2007) Kruzich et al. (2006) Zagreda et al. (1999) Bannerman et al. (2003) Elias and Eleftheriou (1972) Filali and Lalonde (2009) Granholm et al. (2000) Heyser et al. (2000) Meliska et al. (1997) O’Leary and Brown (2009) Schmitt et al. (2004) IDS/EDS, intra-dimensional/extra-dimensional shifting task; MWM, Morris water maze. Frontiers in Neuroscience May 2010 | Volume 4 | Issue 1 | 25