Abstract
Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist) after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting their inhibitory innervation. Endo-N also reduced the expression of vesicular glutamate transporter-1. These results indicate that D2R and PSA-NCAM are important players in the regulation of the structural plasticity of mPFC excitatory neurons. This is relevant to our understanding of the neurobiological basis of schizophrenia, in which structural alterations of pyramidal neurons and altered expression of D2R and PSA-NCAM have been found.
Highlights
Impairments of dopaminergic neurotransmission affecting medial prefrontal cortex function are one of the core features of several psychiatric disorders, including schizophrenia
We showed that the presence of PSA on NCAM is necessary for these D2 receptor (D2R)-induced changes in synapses and inhibitory neurotransmission, since they are blocked when the polysaccharide is ablated from NCAM in the medial prefrontal cortex (mPFC)
Our results indicate that VGLUT1 expression in the mPFC neuropil was not affected by PPHT treatment, neither in the presence nor in the absence of PSA (Control/Control versus Control/PPHT or Endo-N/Control versus Endo-N/PPHT: p = 1.000), but PSA depletion by itself decreased it (Control/Control versus Endo-N/Control: p = 0.028; Control/ Control versus Endo-N/PPHT: p = 0.004) (Figure 2(a))
Summary
Impairments of dopaminergic neurotransmission affecting medial prefrontal cortex (mPFC) function are one of the core features of several psychiatric disorders, including schizophrenia. Recent evidences indicate that, in addition to these neurochemical imbalances, changes in the plasticity of prefrontocortical circuits may underlie the etiopathogenesis of this disorder [3] In this regard, it is important to note that decreased dendritic spine density on mPFC pyramidal neurons is one of the most consistent findings in the brain of schizophrenic patients and animal models of this disorder [4, 5] and after experimental manipulation of mPFC dopamine levels [6]. We showed that the presence of PSA on NCAM is necessary for these D2R-induced changes in synapses and inhibitory neurotransmission, since they are blocked when the polysaccharide is ablated from NCAM in the mPFC Both PPHT treatment and PSA depletion have a strong impact on the perisomatic inhibitory baskets on mPFC pyramidal neurons, increasing the density of perisomatic puncta expressing GAD65/67 and parvalbumin (PV) [13]
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