Abstract
p35 is an activating co-factor of Cyclin-dependent kinase 5 (Cdk5), a protein whose dysfunction has been implicated in a wide-range of neurological disorders including cognitive impairment and disease. Inducible deletion of the p35 gene in adult mice results in profound deficits in hippocampal-dependent spatial learning and synaptic physiology, however the impact of the loss of p35 function on hippocampal in vivo physiology and spatial coding remains unknown. Here, we recorded CA1 pyramidal cell activity in freely behaving p35 cKO and control mice and found that place cells in the mutant mice have elevated firing rates and impaired spatial coding, accompanied by changes in the temporal organization of spiking both during exploration and rest. These data shed light on the role of p35 in maintaining cellular and network excitability and provide a physiological correlate of the spatial learning deficits in these mice.
Highlights
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase structurally homologous to the Cdk family members which modulate the cell cycle
We provide the first analyses of the impact of dysregulation of the Cdk5/p35 complex on in vivo neurophysiology. p35 cKO mice showed significant alterations in both neuronal spiking and spatial coding
We observed an increase in pyramidal cell excitability which resulted in larger place fields with reduced spatial information, suggesting that the loss of p35 leads to impairments in the quality of hippocampal spatial representations in both familiar and novel contexts (Figures 1D–I)
Summary
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase structurally homologous to the Cdk family members which modulate the cell cycle It is unique, in that it is active in post-mitotic neurons and is regulated by two brain specific co-factors, p35 and p39 (Tsai et al, 1994; Tang and Wang, 1996; Takahashi et al, 2005). Post-synaptically, it influences dendritic spine density (Mita et al, 2016) and targets many proteins in the post-synaptic density, including N-methyl-D-aspartate receptors (NMDARs), which are required for synaptic plasticity (Hawasli et al, 2007; Plattner et al, 2014) Given this myriad of diverse functions, it is perhaps not surprising that dysfunction in the Cdk pathway has been linked to cognitive impairments and a number of pathologies, including epilepsy (Wenzel et al, 2001; Putkonen et al, 2011) and Alzheimer’s disease (AD; Lew et al, 1994; Patrick et al, 1999; Yoo and Lubec, 2001)
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