Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility.

While most studies have focused on the role of long-term potentiation in behavior, far less is known about the role of long-term depression (LTD). To examine the potential involvement of LTD in learning and memory, we generated transgenic mice that express a fragment of the SV40 small t antigen known to inhibit protein phosphatase 2A (PP2A). Small t antigen expression blocked both stimulus-induced and chemically induced NMDAR-dependent LTD at Schaffer collateral synapses but did not affect potentiation, depotentiation, or mGluR-dependent LTD. This physiological phenotype was associated with deficits in behavioral flexibility in both the Morris water maze and a delayed nonmatch to place T-maze task, suggesting that NMDAR-dependent LTD is required for behavioral flexibility and may act by weakening previously encoded memory traces when new information is learned.

Understanding and treating "first-episode" schizophrenia.

"First-episode schizophrenia" is a clinical and research term that often is used to emphasize the special issues that arise when working with this patient population. The notion that schizophrenia has an inexorable downhill course or is a deteriorating illness is being challenged by more sophisticated understanding of what happens before the initial episode and new understanding of the interactions between biologic vulnerabilities and specific environmental risk during adolescence and early adulthood, such as marijuana use. While the incidence rate of "first-episode" will make this a relatively small percentage of a usual clinical caseload, it is a critically important time for the future course of the illness. The hope is that proper management during this critical period will favorably influence the long-term trajectory of outcome for this individual patient. A growing body of evidence suggests that certain approaches and interventions are more helpful than others, such as understanding of the overwhelming nature of the experience to patients and families, aiming to achieve a full and broad pharmacologic response to initial antipsychotic therapy, while also being on the lookout for vulnerability and extreme sensitivity to side effects, and to anticipate a high likelihood of premature medication discontinuation. Clinicians and treatment services should try to identify "first-episode" patients in time to be able to anticipate and address these issues.

Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins.

To examine the role of C/EBP-related transcription factors in long-term synaptic plasticity and memory storage, we have used the tetracycline-regulated system and expressed in the forebrain of mice a broad dominant-negative inhibitor of C/EBP (EGFP-AZIP), which preferentially interacts with several inhibiting isoforms of C/EBP. EGFP-AZIP also reduces the expression of ATF4, a distant member of the C/EBP family of transcription factors that is homologous to the Aplysia memory suppressor gene ApCREB-2. Consistent with the removal of inhibitory constraints on transcription, we find an increase in the pattern of gene transcripts in the hippocampus of EGFP-AZIP transgenic mice and both a reversibly enhanced hippocampal-based spatial memory and LTP. These results suggest that several proteins within the C/EBP family including ATF4 (CREB-2) act to constrain long-term synaptic changes and memory formation. Relief of this inhibition lowers the threshold for hippocampal-dependent long-term synaptic potentiation and memory storage in mice.