Valproic acid reduces spatial working memory and cell proliferation in the hippocampus

doi:10.1016/j.neuroscience.2009.11.073

Neuroscience

Volume 166, Issue 1, 10 March 2010, Pages 15-22

https://doi.org/10.1016/j.neuroscience.2009.11.073 Get rights and content

Abstract

Valproic acid (VPA) is widely used clinically, as an anticonvulsant and mood stabilizer but is, however, also known to block cell proliferation through its ability to inhibit histone deacetylase enzymes. There have been a number of reports of cognitive impairments in patients taking VPA. In this investigation we examined the relationship between cognition and changes in cell proliferation within the hippocampus, a brain region where continued formation of new neurons is associated with learning and memory. Treatment of rats by i.p. injection of VPA, reduced cell proliferation in the sub granular zone of the dentate gyrus within the hippocampus. This was linked to a significant impairment in their ability to perform a hippocampus-dependent spatial memory test (novel object location). In addition, drug treatment caused a significant reduction in brain-derived neurotrophic factor (BDNF) and Notch 1 but not doublecortin levels within the hippocampus. These results support the idea that VPA may cause cognitive impairment and provide a possible mechanism for this by reducing neurogenesis within the hippocampus.

Section snippets

Subjects

Adult male Lister Hooded rats (n=20, weight was 220–250 g, Charles River Laboratories) were randomly assigned to control (saline injected) and drug-treated groups. Animals were housed in groups of four under a 12-h light-dark cycle with access to food and water and allowed to habituate in the animal facility for 11 days prior to the start of procedures. Animals were weighed daily and all procedures were carried out in accordance with UK Home Office guidelines and licensing. Animal numbers were

VPA reduces performance in a spatial working memory task

To test the behavioural effect of VPA in a hippocampal dependent task, the performance of drug and control treated animals were compared using the NOL test. Results were assessed by comparing the total time animals spent on objects in either novel or familiar locations in the choice trial, and by calculating the discrimination index for each group. Neither drug-treated nor control groups showed any preference for either object in the familiarization trial (data not shown). In both the

Discussion

Mild to moderate cognitive deficits have been described in adults after use of VPA, the present work confirms that this cognitive effect is reproducible in an animal model. Animals sub-chronically treated with VPA showed an inability to discriminate between an object in a novel location and one in a familiar location. The hippocampus is strongly involved in spatial memory and the NOL test, which uses the natural tendency of rats to explore an object placed in a new position, can only be

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Behavioural NeuroscienceResearch PaperValproic acid reduces spatial working memory and cell proliferation in the hippocampus

Abstract

Section snippets

Subjects

VPA reduces performance in a spatial working memory task

Discussion

Neurosci Biobehav Rev

Seizure

Mol Cell Neurosci

Trends Neurosci

Curr Biol

Behav Brain Res

Behav Brain Res

Neuron

Brain Res

Biol Psychiatry

J Neurosci Methods

Neurosurg Clin North Am

Pharmacol Ther

Neurobiol Learn Mem

Neuroscience

Placenta

Epilepsy Res

Neuron

J Neurol Sci

Epilepsy Res

J Biol Chem

Neuroscience

Neuroscience

Behav Brain Res

Neuroscience

Mech Dev

Cell

Adult neurogenesis: from precursors to network and physiology

Physiol Rev

BDNF is essential to promote persistence of long-term memory storage

Proc Natl Acad Sci U S A

Comparison of valproate and phenobarbital treatment after status epilepticus in rats

Neurology

Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus

Proc Natl Acad Sci U S A

New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment

Eur J Neurosci

Update on the treatment and management of schizophrenia and bipolar disorder

CNS Spectr

Doublecortin expression levels in adult brain reflect neurogenesis

Eur J Neurosci

Valproic acid is associated with cognitive decline in HIV-infected individuals: a clinical observational study

BMC Neurol

Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines

J Neuro Oncol

A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome

Cell

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Proc Natl Acad Sci U S A

Regulation of adult neurogenesis by psychotropic drugs and stress

J Pharmacol Exp Ther

Behavioural Neuroscience
Research Paper
Valproic acid reduces spatial working memory and cell proliferation in the hippocampus