NMDAR antagonists, including phencyclidine, ketamine and MK-801, induce a psychotic reaction in human subjects that resembles many of schizophrenia symptoms leading the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia pathophysiology. These symptoms include the positive, negative, as well as many of the cognitive deficits, including working memory. Furthermore, NMDAR antagonists also reinstate pre- existing symptoms in stabilized schizophrenia patients. Genetic studies have offered further credence to this theory. For instance, a NR1 hypomorph mouse, in which expression of NR1 subunit protein is reduced to 5- 10%, displays deficits in social interaction and impairment in prepulse inhibition of acoustic startle reflex. Yet, it remains to be determined in which developmental stage and/or in which brain cell-types/areas is NMDAR hypofunction necessary to induce schizophrenia-like behaviors. We recently demonstrated that a restricted deletion of NMDAR in corticolimbic interneurons from postnatal 2nd week was sufficient to trigger several behavioral and pathophysiological features in mice that resemble human schizophrenia. Therefore, it provided strong experimental support for the long-standing hypothesis that NMDAR hypofunction in cortical interneurons is a primary site of schizophrenia pathogenesis. However, many genes encoding the NMDAR complex proteins, such as neuregulins, are expressed in both excitatory and inhibitory neurons in the cortex. If the mutation was introduced in these genes, NMDAR hypofunction could occur in every cell including excitatory neurons. Furthermore, it is still unclear which developmental stage is the sensitive period to NMDAR hypofunction. Finally, it is crucial to identify what occurs in the NR1-deleted interneurons and which downstream signaling cascades/circuitries are activated or suppressed following NMDAR deletion. To address these questions using transgenic mice, two major overlapping areas to be investigated in this project are: 1. Define the cell-types and sensitive period for NMDAR hypofunction critical for the manifestation of schizophrenia-like phenotypes. It is critical to narrow down the boundary conditions of NMDAR hypofunction, in order to delineate the downstream pathways of NMDAR hypofunction and to determine which pathways are responsible for later development of the disease. 2. Determine the cellular events that follow NMDAR hypofunction during the sensitive period. It will be crucial to delineate subsequent molecular, cellular and network events following NMDAR hypofunction, in order to develop the new treatments targeted to NMDAR hypofunction for human psychiatric illnesses. These findings derived from this work will yield new insights into the cortical GABAergic interneuron-related pathogenesis and its treatment of schizophrenia.
Schizophrenia, one of the most chronic and disabling mental disorders, is a major focus of research at the National Institute of Mental Health (NIMH). More than 2 million Americans are affected by schizophrenia in any given year, and only one in five recovers completely. The illness, which may impair a person's ability to manage emotions, to socially interact with others, and to think clearly, typically develops in the late teens or early twenties. Symptoms include hallucinations, delusions (positive symptoms), disordered thinking (cognitive symptom), and social withdrawal (negative symptom). During the last two decades, research has led to considerable advances in the treatment of schizophrenia -- primarily in the development of several new medications with fewer side effects. However, the new drugs still insufficiently treat some symptoms, especially cognitive and negative symptoms. Many people with schizophrenia continue to suffer chronically or episodically throughout their lives. In search for better treatments, more intense research needs to be continued to determine the causes and disease process of schizophrenia. This project addresses one of the major pathophysiology theories of schizophrenia - glutamatergic NMDA receptor (NMDAR) hypofunction theory. It is well known that the drugs that block NMDAR channels also evoke psychotomimetic action in healthy human subjects that mimics schizophrenia symptoms. Therefore, NMDAR hypofunction has long been implicated in the pathogenesis of the disease symptoms. However, its underlying mechanisms have remained a mystery until we recently reported that NMDAR hypofunction at cortical and hippocampal GABAergic interneurons are sufficient to elicit the schizophrenia-like phenotypes in mice. The objective of this project is, based on our own finding, to deeper our understanding of the mechanisms of NMDAR hypofunction theory. This project might play an important role in developing new therapeutic targets and define the requisite time of intervention.
