Elsevier

Biological Psychiatry

Volume 62, Issue 3, 1 August 2007, Pages 235-242
Biological Psychiatry

Original Article
Reduction of Corticostriatal Glutamatergic Fibers in Basic Fibroblast Growth Factor Deficient Mice is Associated with Hyperactivity and Enhanced Dopaminergic Transmission

https://doi.org/10.1016/j.biopsych.2006.08.003Get rights and content

Background

Basic fibroblast growth factor (FGF2) plays a crucial role during the development of the cerebral cortex. Mice with a knockout of the FGF2 gene have a reduced number of glutamatergic neurons within the deep layers of the cerebral cortex.

Methods

We used molecular and behavioral analyses to investigate possible alterations in corticostriatal function in FGF2 −/− mice.

Results

We found that FGF2 deficiency leads to decreased expression of presynaptic markers of integrity for glutamatergic fibers in the striatum, namely the membrane excitatory amino acid transporter 3 (EAAT3) and the vesicular glutamate transporter 1 (VGLUT1). The reduction of corticostriatal glutamatergic function in FGF2 −/− mice is associated with enhanced locomotor activity in a novel environment and increased responsiveness to dopaminergic drugs, such as cocaine or amphetamine. The behavioral alterations of FGF2 −/− can be normalized by injection of a low dose of the dopaminergic agonist apomorphine (.1 mg/kg) that reduces dopamine release by acting on presynaptic receptors.

Conclusions

Our data demonstrate that FGF2 −/− mice have an increased tone and responsiveness of the dopaminergic system and suggest that these animals might represent a model to study disorders that are characterized by an imbalance between glutamatergic and dopaminergic neurotransmission.

Section snippets

Animals

Basic fibroblast growth factor wild-type and knockout (129Sv:Black Swiss genetic background) mice strain were obtained from the colony originally generated by Zhou et al. (1998). The mice were derived from five heterozygous pairs (FGF2 +/−) and they were genotyped using the following primers: upper primer, 5’AGG AGG CAA GTG GAA AAC GAA3’; lower primer, 5’CCC AGA AAG CGA AGG AAC AAA3’. The animals were housed five per cage with food and water ad libitum. The housing room was on a 12-hour

Analysis of Corticostriatal Glutamatergic Markers in FGF2 −/− Mice

The FGF2 −/− mice are characterized by morphological alterations in the cerebral cortex with a reduced number of glutamatergic neurons (Korada et al. 2002). Since pyramidal neurons have a profound effect on subcortical regions, we decided to investigate the expression of glutamate transporters in frontal-prefrontal cortex and striatum as an index of integrity of corticostriatal glutamatergic fibers.

First of all, we measured the expression of three plasma membrane glutamate transporters: EAAT1

Discussion

In the present study, we demonstrate that mice with a knockout of the trophic factor FGF2 display behavioral abnormalities that are suggestive of functional enhancement in dopaminergic responsiveness. This may, indeed, occur when the animals are exposed to a novel environment or, more specifically, following injection of dopaminergic drugs (amphetamine or cocaine).

The first set of data show that increased locomotor activity in FGF2 −/− mice is maintained over a 3-day test: such effect appears

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