Title:mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex
Volume: 14
Issue: 4
Author(s): Amber L. LaCrosse, Sara B. Taylor, Natali E. Nemirovsky, Justin T. Gass and Michael F. Olive
Affiliation:
Keywords:
Allosteric modulator, 3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl)benzamide, dendritic spine, fenobam, medial
prefrontal cortex, mGluR5, pyramidal cell, structural plasticity.
Abstract: Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5
metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for
neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However,
only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural
plasticity of dendritic spines in otherwise naïve animals, particularly in brain regions mediating executive function. In the
present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex
(mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-
yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol-
2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats. Following once daily treatment for 10
consecutive days, coronal brain sections containing the mPFC underwent diolistic labeling and 3D image analysis of
dendritic spines. Compared to vehicle treated animals, rats administered fenobam exhibited significant increases in
dendritic spine density and the overall frequency of spines with small (<0.2 μm) head diameters, decreases in frequency of
spines with medium (0.2-0.4 μm) head diameters, and had no changes in frequency of spines with large head diameters
(>0.4 μm). Administration of CDPPB had no discernable effects on dendritic spine density or morphology, and neither
CDPPB nor fenobam had any effect on spine length or volume. We conclude that mGluR5 PAMs and NAMs
differentially affect mPFC dendritic spine structural plasticity in otherwise naïve animals, and additional studies assessing
their effects in combination with cognitive or behavioral tasks are needed.
