Cho Kathleen K A, Hoch Renee, Lee Anthony T, Patel Tosha, Rubenstein John L R, Sohal Vikaas S
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
Neuron. 2015 Mar 18;85(6):1332-43. doi: 10.1016/j.neuron.2015.02.019. Epub 2015 Mar 5.
Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven γ oscillations in cognitive domains at the core of schizophrenia.
γ-氨基丁酸能中间神经元的异常，特别是产生γ（γ；约30 - 120赫兹）振荡的快速放电中间神经元（FSINs），被认为会破坏精神分裂症中依赖前额叶皮质（PFC）的认知功能。尽管精神分裂症患者的γ节律异常，但它们是否直接影响认知仍不清楚。精神分裂症典型的青春期后发病的潜在机制也仍然难以捉摸。我们使用Dlx5/6基因杂合的小鼠来解决这些问题，Dlx5/6基因调控γ-氨基丁酸能中间神经元的发育。在Dlx5/6(+/-)小鼠中，FSINs在青春期后变得异常，这与认知灵活性的出现和任务诱发的γ振荡不足相吻合。抑制对照小鼠的PFC中间神经元会重现这些缺陷，而以γ频率刺激它们则可恢复成年Dlx5/6(+/-)小鼠的认知灵活性。这些促进认知的作用具有频率特异性且持续存在。这些发现阐明了一种机制，即异常的FSIN发育可能导致精神分裂症内表型在青春期后发病。此外，它们还证明了PFC中间神经元驱动的γ振荡在精神分裂症核心认知领域中具有因果性、潜在的治疗作用。
