Cdk5 Is Essential for Amphetamine to Increase Dendritic Spine Density in Hippocampal Pyramidal Neurons

Abstract

Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain. However, little is known about their effects in the hippocampus, where activity-dependent changes in the density of dendritic spine are associated with learning and memory. Recent reports suggest that Cdk5 plays an important role in drug addiction, but its role in psychostimulant’s effects on dendritic spines in hippocampus remain unknown. We used in vivo and in vitro approaches to demonstrate that amphetamine increases dendritic spine density in pyramidal neurons of the hippocampus. Primary cultures and organotypic slice cultures were used for cellular, molecular, pharmacological and biochemical analyses of the role of Cdk5/p25 in amphetamine-induced dendritic spine formation. Amphetamine (two-injection protocol) increased dendritic spine density in hippocampal neurons of thy1-green fluorescent protein (GFP) mice, as well as in hippocampal cultured neurons and organotypic slice cultures. Either genetic or pharmacological inhibition of Cdk5 activity prevented the amphetamine–induced increase in dendritic spine density. Amphetamine also increased spine density in neurons overexpressing the strong Cdk5 activator p25. Finally, inhibition of calpain, the protease necessary for the conversion of p35 to p25, prevented amphetamine’s effect on dendritic spine density. We demonstrate, for the first time, that amphetamine increases the density of dendritic spine in hippocampal pyramidal neurons in vivo and in vitro. Moreover, we show that the Cdk5/p25 signaling and calpain activity are both necessary for the effect of amphetamine on dendritic spine density. The identification of molecular mechanisms underlying psychostimulant effects provides novel and promising therapeutic approaches for the treatment of drug addiction.

The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity

“…To determine how siRNA loss of VAPB or PTPIP51 affects dendritic spine numbers, we transfected neurons with EGFP to reveal neuronal morphology and identify dendrites; such approaches have been used in many other studies e.g. [8, 11, 49]. We then quantified spine numbers in the same dendritic regions of the different treated neurons (20 μm segments after the first branchpoint).…”

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

“…CDK5 is a key second messenger participating in METH-induced behavioral sensitization [ 130 , 242 , 243 ]. Both administration of amphetamines and stimulation of D1R induce a significant increase of CDK5 gene expression and protein levels, which, at molecular level, associates with increased dendritic spine density and hyper-phosphorylation of the cytoskeletal tau protein [ 244 , 245 , 246 ]. In detail, the activation of CDK5 by D1R occurs via proteolysis of p35, the binding partner of CDK5.…”

Mice carrying a schizophrenia-associated mutation of the Arhgap10 gene are vulnerable to the effects of methamphetamine treatment on cognitive function: association with morphological abnormalities in striatal neurons

“…Mushroom-type spines represent a more mature population than other types of spines, and their large head/neck ratio is thought to contribute to their function as stable excitatory synapses [ 63 ]. Of note, repetitive amphetamine or methamphetamine treatment induces behavioral sensitization in mice [ 66 , 67 ], which is accompanied by an increase in mushroom-type spine density in MSNs [ 68 , 69 ]. In the present study, we found an increase in mushroom-type spine density in the striatal and accumbal neurons of Arhgap10 S490P/NHEJ mice that have a higher sensitivity to methamphetamine.…”