Dopamine depletion of the prefrontal cortex induces dendritic spine loss: reversal by atypical antipsychotic drug treatment

Abstract

Dystrophic changes in dendrites of cortical neurons are present in several neuro-psychiatric disorders, including schizophrenia. The mechanisms that account for dendritic changes in the prefrontal cortex (PFC) in schizophrenia are unclear. Cognitive deficits in schizophrenia have been linked to compromised cortical dopamine function, and the density of the PFC dopamine innervation is decreased in schizophrenia. We determined if 6-hydroxydopamine lesions of the ventral tegmental area that disrupt the PFC dopamine innervation cause dystrophic changes in cortical neurons. Three weeks post-operatively we observed a marked decrease in basal dendritic length and spine density of layer V pyramidal cells in the prelimbic cortex; no change was seen in neurons of the motor cortex. We then examined rats in which the PFC dopamine innervation was lesioned and 3 weeks later were started on chronic treatment with an atypical (olanzapine) or typical (haloperidol) antipsychotic drug. Olanzapine but not haloperidol reversed lesion-induced changes in PFC pyramidal cell dendrites. These data suggest that dopamine regulates dendritic structure in PFC neurons. Moreover, the findings are consistent with a decrease in cortical dopaminergic tone contributing to the pathological changes in the cortex of schizophrenia, and suggest that the progressive cortical loss in schizophrenia may be slowed or reversed by treatment with atypical antipsychotic drugs.

Figure 1

6-Hydroxydopamine lesions of the VTA resulted in a marked loss of tyrosine hydroxylase-immunoreactive neurons (right panel) relative to the vehicle-injected control (left panel). There was some sparing of midline DA neurons. The cannula tracts can be seen bilaterally (arrows).

Figure 2

Effects of chronic treatment with haloperidol (H) or olanzapine (O) on total basal dendritic length (top panel) and dendritic spine density (bottom panel) in rats with cortical DA denervation. 6-OHDA lesioned rats that were treated with vehicle (V) had a marked decrease in basal dendritic length and spine density relative to sham-lesioned vehicle-injected animals. Olanzapine but not haloperidol restored basal dendritic length and spine density to levels comparable to those in sham-lesioned vehicle-treated animals. *p≤0.001 relative to sham-lesioned vehicle-treated group; NS, not significant.

Figure 3

Photomicrographs of representative basal (left) and the main shaft of apical (right) dendritic segments in the various treatment groups of the second experiment. The images were obtained from dendritic segments located 60–100 μm distal to the soma. Scale bar=10 μm.

Figure 4

Dendritic spine density as a function of distance from the soma. Spine density in lesioned rats treated with vehicle (LV) was decreased relative to sham-lesioned vehicle-treated (SV) animals starting at 60 μm distal to the soma. Olanzapine administered to lesioned rats (LO) reversed spine density to values comparable to those seen in sham-lesioned vehicle-injected (SV) and sham-lesioned olanzapine-treated (SO) rats, while haloperidol treatment of lesioned rats (LH) had no such effect. ⁺p≤0.01 and ^#p≤0.05 relative to sham-lesioned vehicle-treated rats at the same distance on the dendritic arbor from the soma.

Figure 5

Sholl analysis of dendritic intersections at progressive 20 μm distances from the soma. Animals with 6-OHDA lesions of the VTA treated with vehicle (LV) showed fewer intersections than sham-lesioned vehicle-treated animals (SV) at 40, 60 and 80 μm distal to the soma. Olanzapine treatment of lesioned rats (LO) reversed the decrease in dendritic branching. Lesioned animals treated with haloperidol (LH) also tended to show fewer intersections relative to SV and SH animals, but these effects did not reach statistical significance. ⁺ p≤0.05.

Figure 6

Reconstructions of representative superficial layer V pyramidal cells in sham-lesioned vehicle-treated (SV) animals and 6-OHDA-lesioned rats treated with vehicle (LV), haloperidol (LH) or olanzapine (LO). A marked decrease in the length and complexity of the basal dendritic arbor in the PC of a vehicle-treated lesioned animal can be seen, and one can appreciate a reduction in dendritic spines. Treatment of lesioned animals with haloperidol did not result in any substantial increase in basal dendritic length and branching, but the basal dendrites in a PC from a lesioned animal treated with olanzapine grossly appear to be longer and more complex.