Striatal D2 Receptors Regulate Dendritic Morphology of Medium Spiny Neurons via Kir2 Channels

Abstract

Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that over-expression of dopamine D2 receptors in medium spiny neurons increases their membrane excitability and decreases the complexity and length of their dendritic arbors. These changes can be reversed in the adult animal after restoring D2 receptors to wild-type levels, demonstrating a high degree of structural plasticity in the adult striatum. Increased excitability and decreased dendritic arborization are associated with down-regulation of inward rectifier potassium channels (Kir2.1/2.3). Down-regulation of Kir2 function is critical for the neurophysiological and morphological changes in vivo because virally-mediated expression of a dominant negative Kir2 channel is sufficient to recapitulate the changes in D2 transgenic mice. These findings may have important implications for the understanding of basal ganglia disorders, and more specifically schizophrenia, in which excessive activation of striatal D2 receptors has long been hypothesized to be of pathophysiologic significance.

Dopamine D2 Receptors Regulate Collateral Inhibition between Striatal Medium Spiny Neurons

“…While this correlates with the increased number of functional synapses onto treated D 2 MSNs, it has recently been reported that chronic D 2 R upregulation in vivo in the mouse increases MSN excitability and decreases dendritic arborization by the downregulation of inward rectifying potassium channels (Cazorla et al, 2012). There are several reasons underlying the divergence of our study from these results.…”

“…The drd2-EGFP line in our colony was backcrossed with a C57BL/6 line (Chan et al, 2012) to avoid the abnormalities reported in Kramer et al (2011). The characteristics of MSNs in the presence and absence of treatments were also confirmed in cultures harvested from two separate mouse strains: drd2-cre;rosa26-tdTomato (Madisen et al, 2010) and npy-EGFP;drd1a-tdTomato (Shuen et al, 2008;Partridge et al, 2009).…”

Evidence for Thalamocortical Circuit Abnormalities and Associated Cognitive Dysfunctions in Underweight Individuals with Anorexia Nervosa

“…These deformations may result from a number of factors, including cellular loss, atrophy of neuronal dendritic arbors, demyelination, reduction in somatic size, or loss of afferent input (Sowell et al, 2004). In rodents, it has been shown that increased neuronal excitability is associated with a decrease in dendritic complexity (Cazorla et al, 2012). One previous study has shown hypermetabolism in the thalamus in AN (Takano et al, 2001), which may reflect higher intrinsic neural activity, and potentially explain the thalamic deformation seen in our study as resulting from dendritic atrophy.…”

Dopamine D2 Receptors Regulate the Anatomical Balance of Basal Ganglia Circuitry

“…Specifically, we found that increasing excitability of the indirect pathway is sufficient to induce the growth of bridging collaterals. Chronic upregulation of D2Rs (D2R-OE mice), which increases excitability of the indirect pathway (Cazorla et al, 2012), similarly leads to a higher density of bridging collaterals, a phenotype that is reversed after viral-mediated decrease in excitability of D2R-OE MSNs. In contrast, genetic D2R downregulation (Drd2 −/− ) or chronic treatment with the D2R blocker haloperidol decreases the density of bridging collaterals.…”