What's right with my mouse model? New insights into the molecular and cellular basis of cognition from mouse models of Rubinstein-Taybi Syndrome.

The first gene-targeting studies that examined learning and memory in mice were performed in 1992 (Grant et al. 1992; Silva et al. 1992). The ultimate goal of this new field was to understand the molecular and cellular processes underlying normal cognition and how they may be altered in disease states. In the years since these pioneering studies, well over 100 different molecules have been identified that are essential to or modulate learning and memory. Despite this rapid progress, the translation of these basic findings to human cognitive disorders has been slow. However, this may be changing. In this issue, Wood et al. (2005) use a combination of approaches to examine the molecular, cellular, and systems basis of a learning and memory disorder. Together with recent results from other groups, these findings not only provide valuable insights into cognition, but represent important first steps toward developing treatments for cognitive disorders. Rubinstein-Taybi syndrome (RTS) is a human genetic disorder characterized by mental retardation and physical abnormalities. RTS is caused by chromosomal rearrangements, microdeletions, and point mutations in one copy of the gene encoding CREB-binding protein (CBP) (Petrij et al. 1995). CBP is a multidomain protein that serves as an essential transcription coactivator for many transcription factors such as CREB, c-Jun and c-Fos (Chrivia et al. 1993). It is thought that CBP facilitates transcription by coupling transcription-factor recognition to chromatin remodeling (McManus et al. 2001). First, CBP serves as a physical link between DNA-binding transcription factors and the basal transcriptional machinery. Second, CBP facilitates transcription through intrinsic histone acetyltransferase (HAT) activity that opens up condensed DNA, thereby allowing the transcriptional machinery greater access. CBP was first identified by its ability to interact with an activated (phosphorylated at Ser133) form of CREB (Chrivia et al. 1993). Numerous studies from invertebrate and vertebrate species implicate CREB-mediated transcription in memory and synaptic plasticity (Dash et al. 1990; Bourtchuladze et al. 1994; Yin et al. 1994; Bartsch et al. 1995; Josselyn et al. 2001; Kida et al. 2002). These findings led to the notion that disruption of CREB:CBP function contributes to the cognitive dysfunction observed in patients with RTS. Soon after the gene responsible for RTS was identified, two mouse models of RTS were generated. The first model is a conventional knockout with a heterozygous null mutation of CBP (CBP ) (Tanaka et al. 1997). The second model has an insertional mutation in one cbp allele that produces CBP protein with a C-terminal truncation (CBP ) (Oike et al. 1999). This truncated protein lacks the HAT domain and may function as a dominant negative. Mice homozygous for either of these germline mutations die prenatally, indicating that CBP performs vital developmental functions. However, heterozygous mice are viable and show phenotypic overlap with RTS patients, including skeletal and cardiac abnormalities, growth retardation, and memory deficits (Tanaka et al. 1997; Oike et al. 1999; Alarcon et al. 2004) (see Table 1). In both of these mouse models, however, CBP function is compromised throughout development and throughout the body. Therefore, the possible contributions of CBP to adult memory processes cannot be adequately assessed. To directly determine the effects of disrupting CBP function on synaptic plasticity and memory in adult brains, Wood et al. (2005) developed transgenic mice in which a truncated form of CBP (CBP 1) is expressed only in postnatal forebrain neurons. The truncated form of CBP retains the N terminus (including the binding site for a subset of transcription factors that normally bind to CBP, such as CREB) but lacks the C terminus of fulllength CBP (including the HAT domain that is important for chromatin remodeling and transcriptional activation). Therefore, this truncated protein should disrupt the function of a subset of CBP-binding transcription factors. To test this, these researchers used cell cultures and hippocampal microarrays. Wood et al. (2005) observed that CBP 1 does not impair the basal transcription of several “housekeeping genes”, but severely disrupts gene expression normally induced by CREB activation. Importantly, this finding is in keeping with results showing that mutations of the CBP HAT domain in several RTS cases are associated with marked impairments in CREB-mediated transcription (Kalkhoven et al. 2003). To direct expression of CBP 1 to postnatal excitatory neurons in the forebrain (including the hippocampus, cortex, and amygdala), the transgene was placed under the control of the CaMKII promoter. The resulting CBP 1 transgenic mice appear free from developmental abnormalities and have normal weight, locomotor activity, and anxiety levels. Wood et al. (2005) assessed the effects of overexpressing the truncated form of CBP on shortand long-term memory using a fear-conditioning paradigm. In this task, an aversive footshock is delivered following placement in a novel chamber (contextual fear conditioning) or delivery of a tone (cued fear conditioning). Contextual fear conditioning involves both the hippocampus and amygdala, while cued fear conditioning critically involves the amygdala (Fanselow 2000; LeDoux 2000). CBP 1 transgenic mice show a specific deficit in long-term memory (LTM), but intact short-term memory (STM), following contextual fear conditioning. This result agrees with extensive evidence that LTM, but not STM, requires the transcription and translation of new proteins (Davis and Squire 1984; Matthies 1989). Perhaps surprisingly, no impairment was observed following cued fear conditioning. The authors hypothesize that this may be due to lower expression of CBP 1 in the amygdala of these transgenic mice or differences between the sensitivity of the amygdala and hippocampus to disruptions of CBP function. E-mail sheena.josselyn@sickkids.ca; fax (416) 813-6846. Article and publication are at http://www.learnmem. org/cgi/doi/10.1101/ lm.93505.