TY - JOUR T1 - Loss of CDKL5 in glutamatergic neurons disrupts hippocampal microcircuitry and leads to memory impairment in mice JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.0539-17.2017 SP - 0539-17 AU - Sheng Tang AU - I-Ting Judy Wang AU - Cuiyong Yue AU - Hajime Takano AU - Barbara Terzic AU - Katarina Pance AU - Jun Y. Lee AU - Yue Cui AU - Douglas A. Coulter AU - Zhaolan Zhou Y1 - 2017/07/03 UR - http://www.jneurosci.org/content/early/2017/07/03/JNEUROSCI.0539-17.2017.abstract N2 - CDKL5 deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking cyclin-dependent kinase-like 5 (CDKL5) display multiple behavioral abnormalities reminiscent of the disorder, but the cellular origins of these phenotypes remain unclear. Here, we find that ablating CDKL5 expression specifically from forebrain glutamatergic neurons impairs hippocampal-dependent memory in male conditional knockout mice. Hippocampal pyramidal neurons lacking CDKL5 show decreased dendritic complexity but a trend toward increased spine density. This morphological change is accompanied by an increase in the frequency of spontaneous miniature EPSCs and interestingly, miniature IPSCs. Using voltage-sensitive dye imaging to interrogate the evoked response of the CA1 microcircuit, we find that CA1 pyramidal neurons lacking CDKL5 show hyperexcitability in their dendritic domain that is constrained by elevated inhibition in a spatially and temporally distinct manner. These results suggest a novel role for CDKL5 in the regulation of synaptic function and uncover an intriguing microcircuit mechanism underlying impaired learning and memory.SIGNIFICANCE STATEMENTCDKL5 deficiency is a severe neurodevelopmental disorder caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene. While Cdkl5 constitutive knockout mice have recapitulated key aspects of human symptomatology, the cellular origins of CDKL5 deficiency-related phenotypes are unknown. Here, using conditional knockout mice, we show that hippocampal-dependent learning and memory deficits in CDKL5 deficiency have origins in glutamatergic neurons of the forebrain and that loss of CDKL5 results in the enhancement of synaptic transmission and disruptions in neural circuit dynamics in a spatially and temporally specific manner. Our findings demonstrate that CDKL5 is an important regulator of synaptic function in glutamatergic neurons and serves a critical role in learning and memory. ER -