Dataset Information

D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex.

ABSTRACT: Two distinct defects are thought to be important for the pathophysiology of schizophrenia. One is an increase of D2 receptors (D2Rs) in the striatum and another is a decrease in the GABAergic function in the prefrontal cortex (PFC). Whether these two defects are functionally linked is not known. We previously reported that selective overexpression of D2Rs in the striatum of the mouse causes behavioral abnormality associated with PFC functions. Using patch-clamp recording, we find that overexpression of D2Rs in the striatum affects inhibitory transmission in the PFC and dopamine (DA) sensitivity. The overexpression of D2Rs in the striatum caused an increase in frequency of spontaneous excitatory postsynaptic currents (EPSCs) in layer V pyramidal neurons, whereas their neuronal excitability was unaffected. In contrast, both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) were significantly decreased in these mice, indicating a reduced inhibitory transmission. Furthermore, in D2R transgenic mice the dopaminergic modulation of evoked IPSCs was shifted, with reduced sensitivity. The change in dopamine sensitivity in the PFC of D2R transgenic mice appears specific for D2Rs because in D2R transgenic mice the effects of D2 agonist but not D1 agonist, on both evoked IPSCs and EPSCs, were reduced. Together, these results indicate that overexpression of D2Rs in the striatum leads to a functional deficit in the GABAergic system. These results provide a functional link between D2R overexpression and GABAergic inhibition in the PFC and suggest that the postulated deficit in GABAergic function in schizophrenia could be secondary to alterations in the striatal dopamine system.

SUBMITTER: Li YC

PROVIDER: S-EPMC3141950 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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.

Dataset Information

D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets