Reichel Judith M, Nissel Sabine, Rogel-Salazar Gabriela, Mederer Anna, Käfer Karola, Bedenk Benedikt T, Martens Henrik, Anders Rebecca, Grosche Jens, Michalski Dominik, Härtig Wolfgang, Wotjak Carsten T
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
Paul Flechsig Institute for Brain Research, University of Leipzig Leipzig, Germany.
Front Behav Neurosci. 2015 Jan 13;8:452. doi: 10.3389/fnbeh.2014.00452. eCollection 2014.
GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.
γ-氨基丁酸能中间神经元对于整个中枢神经系统中兴奋性和抑制性冲动之间的功能平衡至关重要。这种平衡的破坏会导致各种神经或神经精神疾病，如癫痫或精神分裂症。精神分裂症在临床上由阴性症状（如抑郁）和阳性症状（如幻觉）以及认知功能障碍来定义。γ-氨基丁酸能中间神经元被认为在精神分裂症的病因和进展中起核心作用；然而，症状发展的具体机制和时间线以及皮质和海马γ-氨基丁酸能中间神经元在精神分裂症相关症状病因中的不同参与情况仍未得到最终解决。先前的研究表明，通过体外和体内与皂草素偶联的抗囊泡γ-氨基丁酸转运体抗体（SAVAs），可以在成年小鼠中选择性地耗尽γ-氨基丁酸能中间神经元。鉴于它们参与精神分裂症相关疾病的病因，我们在成年雄性C57BL/6N小鼠的内侧前额叶皮质（mPFC）和背侧海马（dHPC）中消融了γ-氨基丁酸能中间神经元。随后，我们评估了长期（>14天）和短期（<14天）γ-氨基丁酸能神经元耗竭后焦虑、感觉处理、多动和认知方面的变化。mPFC中长期γ-氨基丁酸能神经元耗竭导致感觉运动门控降低和认知灵活性受损。值得注意的是，在dHPC水平进行相同的处理完全消除了空间学习能力。dHPC中短期γ-氨基丁酸能神经元耗竭显示出短暂的多动表型以及在获取空间记忆方面的明显损害。相比之下，空间记忆的回忆不受相同干预的影响。这些发现强调了功能性局部γ-氨基丁酸能网络对于海马依赖性空间记忆编码而非回忆的重要性。
