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

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.SIGNIFICANCE STATEMENT Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although Cdkl5 constitutive knock-out mice have recapitulated key aspects of human symptomatology, the cellular origins of CDKL5 deficiency-related phenotypes are unknown. Here, using conditional knock-out 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.

Pubmed ID: 28674172 RIS Download

Mesh terms: Animals | Glutamates | Hippocampus | Male | Memory | Memory Disorders | Mice | Mice, Inbred C57BL | Mice, Knockout | Nerve Net | Neurons | Protein-Serine-Threonine Kinases

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Associated grants

  • Agency: NINDS NIH HHS, Id: F30 NS100433
  • Agency: NINDS NIH HHS, Id: R01 NS038572
  • Agency: NIGMS NIH HHS, Id: T32 GM007170
  • Agency: NICHD NIH HHS, Id: T32 HD083185
  • Agency: NIMH NIH HHS, Id: T32 MH017168
  • Agency: NICHD NIH HHS, Id: U54 HD086984

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FilamentTracer

A software application that automatically detects neurons (dendritic trees, axons and spines), microtubules, and other filament-like structures in 2D, 3D and 4D. Imaris FilamentTracer uses strategies that involve an optimal combination of automated analysis and operator decision. The choice of the best method is an essential element in optimizing efficiency. FilamentTracer allows the choice between four complementary tracing strategies ranging from manual to automatic and utilizes a creation wizard to easily guide the user through the creations steps. It has been specifically designed to deal with the complex problem of spine analysis over time.

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