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Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits.

ABSTRACT: To understand the role of specific fibroblast growth factor receptors (FGFRs) in cortical development, we conditionally inactivated Fgfr2 or both Fgfr1 and Fgfr2 [Fgfr2 conditional knock-out (cKO) or double knock-out mice, respectively] in radial glial cells of the dorsal telencephalon. Fgfr1 and Fgfr2 are necessary for the attainment of a normal number of excitatory neurons in the cerebral cortex. The action of FGF receptors appears to be through increasing self-renewal of neuronal precursors within the ventricular zone. Volume measurements, assessments of excitatory neuron number, and areal marker expression suggested that the proper formation of the medial prefrontal cortex (mPFC) depends on the function of Fgfr2, whereas Fgfr1 together with Fgfr2 control excitatory cortical neuron development within the entire cerebral cortex. Fgfr2 cKO mice had fewer and smaller glutamate synaptic terminals in the bed nuclei of the stria terminalis (BST), a projection area for mPFC cortical neurons. Furthermore, Fgfr2 cKO mice showed secondary decreases in GABAergic neurons in the BST and septum. These data demonstrate that FGFR2 signaling expands the number of excitatory neurons in the mPFC and secondarily influences target neurons in subcortical stations of the limbic system.

SUBMITTER: Stevens HE

PROVIDER: S-EPMC2868832 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits.

Stevens Hanna E HE Smith Karen M KM Maragnoli M Elisabetta ME Fagel Devon D Borok Erzsi E Shanabrough Marya M Horvath Tamas L TL Vaccarino Flora M FM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100401 16

To understand the role of specific fibroblast growth factor receptors (FGFRs) in cortical development, we conditionally inactivated Fgfr2 or both Fgfr1 and Fgfr2 [Fgfr2 conditional knock-out (cKO) or double knock-out mice, respectively] in radial glial cells of the dorsal telencephalon. Fgfr1 and Fgfr2 are necessary for the attainment of a normal number of excitatory neurons in the cerebral cortex. The action of FGF receptors appears to be through increasing self-renewal of neuronal precursors w ...[more]

PMID: 20410112

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Project description:Decreased expression of dopamine D2 receptors (D2R), dysfunction of inhibitory neurotransmission and impairments in the structure and connectivity of neurons in the medial prefrontal cortex (mPFC) are involved in the pathogenesis of schizophrenia and major depression, but the relationship between these changes remains unclear. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, may serve as a link. This molecule is expressed in cortical interneurons and dopamine, via D2R, modulates its expression in parallel to that of proteins related to synapses and inhibitory neurotransmission, suggesting that D2R-targeted antipsychotics/antidepressants may act by affecting the plasticity of mPFC inhibitory circuits. To understand the role of PSA-NCAM in this plasticity, rats were chronically treated with a D2R agonist (PPHT) after cortical PSA depletion. PPHT-induced increases in GAD67 and synaptophysin (SYN) neuropil expression were blocked when PSA was previously removed, indicating a role for PSA-NCAM in this plasticity. The number of PSA-NCAM expressing interneuron somata also increased after PPHT treatment, but the percentages of these cells belonging to different interneuronal subpopulations did not change. Cortical pyramidal neurons did not express PSA-NCAM, but puncta co-expressing this molecule and parvalbumin could be found surrounding their somata. PPHT treatment increased the number of PSA-NCAM and parvalbumin expressing perisomatic puncta, but decreased the percentage of parvalbumin puncta that co-expressed SYN. PSA depletion did not block these effects on the perisomatic region, but increased further the number of parvalbumin expressing puncta and increased the percentage of puncta co-expressing SYN and parvalbumin, suggesting that the polysialylation of NCAM may regulate perisomatic inhibition of mPFC principal neurons. Summarizing, the present results indicate that dopamine acting on D2R influences structural plasticity of mPFC interneurons and point to PSA-NCAM as a key player in this remodeling.

Project description:Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

Dataset Information

Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits.

Publications

Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits.

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