Regulation of Hippocampal and Behavioral Excitability by Cyclin-Dependent Kinase 5

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that has been implicated in learning, synaptic plasticity, neurotransmission, and numerous neurological disorders. We previously showed that conditional loss of Cdk5 in adult mice enhanced hippocampal learning and plasticity via modulation of calpain-mediated N-methyl-D-aspartic acid receptor (NMDAR) degradation. In the present study, we characterize the enhanced synaptic plasticity and examine the effects of long-term Cdk5 loss on hippocampal excitability in adult mice. Field excitatory post-synaptic potentials (fEPSPs) from the Schaffer collateral CA1 subregion of the hippocampus (SC/CA1) reveal that loss of Cdk5 altered theta burst topography and enhanced post-tetanic potentiation. Since Cdk5 governs NMDAR NR2B subunit levels, we investigated the effects of long-term Cdk5 knockout on hippocampal neuronal excitability by measuring NMDAR-mediated fEPSP magnitudes and population-spike thresholds. Long-term loss of Cdk5 led to increased Mg2+-sensitive potentials and a lower threshold for epileptiform activity and seizures. Biochemical analyses were performed to better understand the role of Cdk5 in seizures. Induced-seizures in wild-type animals led to elevated amounts of p25, the Cdk5-activating cofactor. Long-term, but not acute, loss of Cdk5 led to decreased p25 levels, suggesting that Cdk5/p25 may be activated as a homeostatic mechanism to attenuate epileptiform activity. These findings indicate that Cdk5 regulates synaptic plasticity, controls neuronal and behavioral stimulus-induced excitability and may be a novel pharmacological target for cognitive and anticonvulsant therapies.

Forebrain-specific deletion of Cdk5 in pyramidal neurons results in mania-like behavior and cognitive impairment

“…However, both Cdk5 mutant mouse models exhibit seizures. Hawasli et al proposed that an acute increase in p25 levels in their mouse model during seizure activity is a compensatory mechanism, and long-term loss of Cdk5 also results in a reduction in p25 (Hawasli et al, 2009). While we have not yet examined the relationship of p35 to p25 levels in our Cdk5f/f/CW2 animals, we cannot exclude the possibility that cleavage of p35 to p25 is altered under neurotoxic conditions.…”

Attention-Deficit/Hyperactivity Phenotype in Mice Lacking the Cyclin-Dependent Kinase 5 Cofactor p35

“…As a noninvasive metabolic imaging technique with clinical acceptance, FDG-PET demonstrated clear perturbations in glucose metabolism, prompting our further study of the effects of p35 KO on mesocorticolimbic circuitry and function. The hypermetabolic brain activity of p35 −/− mice may result from reduced Cdk5/p35-dependent inhibition of neuronal excitability (62-63). We also revealed that p35 KO caused increased mesolimbic connectivity and PFC neurotransmitter content possibly necessitating an increase in supportive energy expenditure.…”

Functional and mechanistic exploration of an adult neurogenesis‐promoting small molecule

“…Acute coronal brain slices and DG GCL recordings were performed as described previously (40). Briefly, recordings were performed on 400‐μm brain slices kept at 32°C in artificial cerebrospinal fluid (ACSF) containing 124 mM NaCl, 2 mM KCl, 2 mM MgSO 4 , 1.25 mM NaH 2 PO 4 , 26 mM NaHCO 3 , 2 mM CaCl 2 , 10 mM glucose, and a gas mixture of 95% O 2 and 5% CO 2 .…”