Schizophrenia Research Forum - A Catalyst for Creative Thinking


Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007 Oct 17 ; 27(42):11424-30. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 29 November 2007
Posted 29 November 2007

What struck me most about the paper of Lodge and Grace is the overall consistency of the body of work between the preclinical and clinical observations, even down to the effect size for the dopaminergic alteration. Dopamine release in schizophrenia is at least double that in controls; whether measured after amphetamine (on average 17 percent displacement of the benzamide radiotracer versus 7 percent in controls) (Laruelle et al., 1999) or at baseline (19 percent D2 occupancy by dopamine in patients versus 9 percent in controls) (Abi-Dargham et al., 2000), the increase in dopamine activity in VTA of the MAM rats reported here is also a doubling of what is measured in saline-treated rats.

This work presents an important contribution to the field because it clarifies the role of the hippocampus in one of the cardinal features of the disorder as modeled in MAM rats. The fact that MAM treatment is one of the most valid animal models of schizophrenia—it replicates many of the disturbances, neurochemical, cellular, dendritic, morphometric, and behavioral, observed in schizophrenia—makes the finding very compelling.

The role of an abnormal hippocampal node in an important circuit central to the pathophysiology of schizophrenia has face validity: there are now many converging lines of evidence in patients with schizophrenia for alterations in hippocampal volume, cytoarchitecture, function, and neurochemical indices. What this paper presents that is unique is evidence, in a valid model of schizophrenia, for an etiological link between the faulty hippocampus and the faulty VTA. The next step will be to test an association between pathology of the hippocampus and that of the VTA and related striatal output in patients with schizophrenia. This is a study we currently are conducting, and is an example of translational research where a theory gets support and contributions by going back and forth between preclinical and clinical testing. If there is an association in the same patients between the hippocampal pathology and dopamine dysregulation, it will suggest that what is described for the MAM model here may be true for schizophrenia, too, i.e., that the pathology of the dopamine system is driven by a faulty hippocampal input.

References:

Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56-72. Abstract

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97:8104-8109. Abstract

View all comments by Anissa Abi-DarghamComment by:  Elizabeth Tunbridge
Submitted 20 December 2007
Posted 20 December 2007
  I recommend the Primary Papers

In their recent paper Lodge and Grace elegantly demonstrate that hyperactivity of the ventral hippocampus underlies the elevated number of spontaneously active ventral tegmental dopamine neurons, and the concomitant increase in amphetamine-induced locomotor activity, found in MAM-treated rats. Since neonatal MAM treatment recapitulates some of the neurochemical, anatomical, and behavioral abnormalities associated with schizophrenia, these findings raise the possibility that the abnormal subcortical dopamine function associated with this disorder might also result from hippocampal dysfunction.

These findings are consistent with a wealth of evidence suggesting that the hippocampus is a prominent site of dysfunction in the schizophrenic brain (reviewed in Harrison, 2004), and it will be exciting to see the results of the clinical studies described by Anissa Abi-Dargham above.

In the future, it will be important to try to integrate these findings with other models aiming to explain the subcortical dopaminergic hyperactivity seen in schizophrenia. One well-known hypothesis is that these abnormalities might result from hypofunction of the prefrontal cortex (PFC; Weinberger, 1987; Bertolino et al., 2000). Animal studies demonstrate that PFC activity impacts on striatal dopamine function (e.g., Shim et al., 1996) and vice versa (Kellendonk et al., 2006). Thus, it will be of interest to assess the relative contributions of hippocampal and prefrontal dysfunction to these subcortical abnormalities in schizophrenia. Such investigations will necessarily involve the use of both patient populations and appropriate animal model systems. A difficult question will be to establish whether any one of these three regions represents a site of a primary “lesion” in schizophrenia or, perhaps more likely, whether their dysfunction reflects abnormalities in the circuits that link them.

References:

Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology. 2000 Feb;22(2):125-32. Abstract

Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl). 2004 Jun;174(1):151-62. Epub 2004 Mar 6. Review. Abstract

Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006 Feb 16;49(4):603-15. Abstract

Shim SS, Bunney BS, Shi WX. Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology. 1996 Nov;15(5):437-41. Abstract

Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987 Jul;44(7):660-9. Abstract

View all comments by Elizabeth Tunbridge