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Dr. Nakazawa, Unit Chief
Cortical GABAergic circuits are highly immature at birth and develop slowly and incrementally through adolescence. For instance, maturation of Ca2+-binding protein parvalbumin (PV)-containing chandelier and basket cells begins during the second postnatal week in rodents, and extends into late adolescence both in rodents and primates. Because maturation of excitatory circuits relies on inhibition mediated by GABA released from these neurons, disturbing GABAergic circuit development could lead to a variety of neurodevelopmental disorders. However, the factors which control postnatal maturation of cortical circuits are poorly understood.
Our research objective is to understand the mechanisms underlying the postnatal development of cortical circuitry and how disruption of normal development can lead to neuropsychiatric disorders. We are particularly interested in the differential roles of cortical and hippocampal GABAergic neurons and excitatory principal neurons in the refinement of the cortical circuitry and function. This Unit has focused on the roles of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor channels (NMDAR) in learning and memory for many years. Interestingly, NMDARs are also prominently expressed in cortical interneurons from the early postnatal period to adulthood, and, at the cellular level, play a pivotal role in shaping firing properties and spike timing in interneurons. We hypothesized that NMDARs in corticolimbic interneurons may actively participate in proper maturation of cortical GABAergic circuitry. To this end, we created a conditional NMDAR knockout mouse strain, in which early postnatal deletion of NR1, an essential subunit of the functional NMDAR channel, was exclusively targeted to GABAergic neurons in cortex and hippocampus using the Cre/loxP system. We found that deletion of NMDARs in a subset of corticolimbic interneurons in early postnatal development results in dysfunction of GABAergic circuits and the emergence of schizophrenia-related symptoms after adolescence (Belforte JE et al, submitted). Notably, the mutants exhibit positive symptoms such as psychomotor agitation and negative symptoms such as a reduced preference for sweet solution and deficits in nesting/mating, which mirror anhedonia and social withdrawal. In addition, the mutant mice have cognitive-like symptoms including impairments in spatial working memory and short-term social memory. Impaired sensorimotor gating, demonstrated by the decreased PPI of the startle reflex, was also observed. In addition, the NR1-deleted cortical GABAergic neurons exhibited reduced GAD67 and PV levels, consistent with reduced expression of these markers in the postmortem cortex of schizophrenic individuals. Disinhibition of cortical excitatory neurons and reduced neuronal synchrony in the mutants is also consistent with hyperactivity of the dorsolateral prefrontal cortex, a finding that was demonstrated during a working memory task in individuals with schizophrenia. Interestingly, many mutant phenotypes were first observed at an age of >12 weeks, suggesting there is a latency period between NR1 knockout and the emergence of these phenotypes. This latency period resembles the premorbid stage that precedes the emergence of symptoms, which is characteristic of several major psychiatric disorders, particularly schizophrenia. Social isolation-induced stress exacerbated the expression of these phenotypes in the mutant, similar to stress-induced precipitation of psychiatric illnesses in humans and which is particularly well-characterized in schizophrenia. Notably, no such abnormalities were detected when the conditional knockout of NMDARs occurred after adolescence in the same cell population, suggesting a critical period for the development of psychiatric symptoms arising from dysregulation of inhibitory circuitry.
Currently, we are focusing on three major topics following our recent research advance. First, we will try to elucidate the underlying molecular mechanisms that lead to schizophrenia-related phenotypes in the mutants. In particular, we are interested in the stress-related regulation of GABA-mediated inhibition onto excitatory cells. Second, one of our key findings was that there was no apparent phenotype when NMDARs are deleted after adolescence. We are trying to understand genetic and epigenetic factor(s) controlling this critical period for emergence of schizophrenia-like phenotypes. Third, by creating other interneuron-specific knockout mutants, we will try to dissect out the phenotypes into several signaling pathway. Our ultimate research goal is to understand the neural basis of ‘neuropsychiatric states’ during mouse behavior by in vivo behavioral and physiological monitoring.
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