Behavioral phenotype

Picciotto, M.R., Caldarone, B J., Brunzell, D.H., Zachariou, V., Stevens, T.R., King, S.L. Neuronal nicotinic acetylcholine receptor subunit knockout mice physiological and behavioral phenotypes and possible clinical implications. Pharmacol. Ther. 92 89, 2001. 

Keywords Anxiety Animal model Behavioral phenotyping Ethological testing... 

Using a large-scale screening procedure for behavioral phenotyping in mice, the first behavioral screenings in ENU-mutagenesis mice demonstrated that it is possible to reliably identify and dissociate mutants with alterations in... 

Studies in mice with a targeted inactivation of other 5-HT receptor sub-types, such as the S-HTsa and 5-HT7, or a transgenic line that overexpresses 5-HT3, demonstrate that these receptors modulate the activity of neural circuits involved specifically in exploratory and reward-related behavior. When exposed to novel environments, KO mice lacking the S-HTsa exhibit increased exploratory activity and an attenuated stimulatory effect of lysergic acid diethylamide (LSD) on exploratory activity but no change in anxiety-related behavior (Grailhe et al. 1999), whereas S-HTy KO mice do not express any overt behavioral phenotype at all (Hedlund et al. 2003). 

Table 2 Functional serotonergic gene variations associated with behavioral phenotype, psychopathology, and psychiatric disorders...

Crawley JN, Paylor R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31 197-211... 

Stress is thought to be an important factor in the pathophysiology of depression and anxiety disorders. It seems possible that the reduced stress reactivity of NKl receptor- and tael-deficient mice has contributed to the behavioral phenotypes observed in the animal models of anxiety and depression. 

Mutant mice lackingNPY showincreased anxiety-relatedbehavior (Palmiter et al. 1998) a full description of the behavioral phenotype of NPY receptor-null mutant mice is not available yet. However, data from Y2 receptor-null mutants support an anti-stress activity of NPY (Tschenett et al. 2003). In addition to the anxiolytic and anti-stress effects of NPY, a relationship to alcohol intake has been described. Voluntary ethanol consumption is increased in NPY and Yi receptor-null mutant mice, whereas either NPY overexpression or potentiation of NPY signaling through blockade of Y2 receptors suppresses rodent alcohol intake (Thiel et al. 1998,2002 Thorsell et al. 2002). Thus, in addition to anxiety and depression, alcohol dependency may be a promising clinical field for newly developed NPY receptor hgands. 

Crawley, J. N. (1999) Behavioral phenotyping of transgenic and knockout mice experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 835, 18-26. 

Crawley, J. N., Belknap, J. K., Collins, A., Crabbe, J. C., Frankel, W., et al. (1997) Behavioral phenotypes of inbred mouse strains implications and recommendations for molecular studies. Psychopharmacology (Berl) 132, 107-124. 

As genetic background greatly influences behavioral phenotypes in mice, comparative studies must take this into account. The use of inbred mice substantially decreases within-subject variation and also provides valuable insight into the neurobiological mechanisms that modulate specific phenotypes. The most updated detailed nomenclature for mouse strains should be used, and mice should be obtained from certified vendors or other reliable sources to ensure comparability of results between laboratories. In contrast, outbred mice do not seem to present similar benefits, and therefore, may yield more confounded results. 

The genes for all three a-LTX receptors have been knocked out in mice, and these mutations are not lethal. NRX la knockout mice show no obvious behavioral phenotype (Geppert et al. 1998). LPH1 knockout causes social problems in mice (Tobaben et al. 2002), consistent with LPH1 involvement in schizophrenia (Chen and Chen 2005). PTPo knockout leads to developmental abnormalities in the nervous system and outside it (Meathrel et al. 2002 Batt et al. 2002). 

Cravatt et al. (2001) generated mutant mice lacking the faah gene (FAAH / mice) and characterized by altered nociceptive threshold, enhanced memory extinction, and increased sensitivity to the effects of exogenously administered ECs (Cravatt et al., 2001 Varvel et al., 2007). Such behavioral phenotype is compatible with the higher AEA levels measured in these mice (Cravatt et al., 2001). 

Receptor knocked out Behavioral phenotype Proposed neural circuit underlying phenotype... 

An alternative, although not necessarily mutually exclusive, hypothesis is that the SERT KO anxiety-like behavioral phenotype arises from developmental alterations in these mice. In line with this hypothesis, inhibiting SERT with SSRIs during a transient early postnatal period causes a variety of affective changes later in the resultant adult animals that are generally similar to those seen in SERT KO mice (194,195). Furthermore, the effects of neonatal SSRI exposure are specifically the result of SERT blockade because they are absent in mice genetically deficient in SERT (196). 

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