Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking 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 knock-out 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.

Chemical genetic identification of CDKL 5 substrates reveals its role in neuronal microtubule dynamics

“…Despite its role in cytoskeletal and cargo transport regulation, we did not find major differences in dendrite morphologies of CDKL5 KO mice in culture or in vivo . Our results are in agreement with reports where subtle reductions in dendrite length were observed in CDLK5‐deficient pyramidal neurons from CDKL5 KO mice (Tang et al , ; Zhou et al , ), but contrast with major dendritic alterations (Amendola et al , ). Modest reductions in dendrite arborization could be caused by compromised anterograde trafficking in CDKL5 KO dendrites.…”

Molecular and Synaptic Bases of CDKL5 Disorder

“…However, in conditional knockout mice in which CDKL5 was ablated specifically from forebrain excitatory neurons, a trend toward an increase in spine density and volume was observed (Tang et al, 2017). In support of this morphological change, the frequency of spontaneous miniature EPSC was increased (Tang et al, 2017). The cause of this discrepancy is not clear.…”

“…In one line, the total length of apical dendrites was significantly reduced in cortical and hippocampal CA1 pyramidal neurons , and in dentate gyrus granule cells Fuchs et al, 2015). In another mouse line, the dendritic complexity of CA1 pyramidal neurons was decreased although the total length was not significantly changed (Tang et al, 2017). Importantly, CDKL5 is not only required, but sufficient to promote dendrite growth.…”

“…The expression levels of several postsynaptic markers, such as PSD‐95 and homer were reduced (Pizzo et al ., ). However, in conditional knockout mice in which CDKL5 was ablated specifically from forebrain excitatory neurons, a trend toward an increase in spine density and volume was observed (Tang et al ., ). In support of this morphological change, the frequency of spontaneous miniature EPSC was increased (Tang et al ., ).…”

“…Accumulating pieces of evidence also suggest that CDKL5 plays a role in synaptic function in the adult brain. Several mouse models with CDKL5 deficiency have been generated (Wang et al, 2012;Amendola et al, 2014;Jhang et al, 2017;Tang et al, 2017;Okuda et al, 2018). These mice display a broad spectrum of behavior abnormities, including limb clasping, changes in locomotion, abnormal eye tracking, impaired learning and memory, and autistic-like phenotypes (Table 1).…”