Neurobiological evidence for thalamic, hippocampal and related glutamatergic abnormalities in bipolar disorder: a review and synthesis.

The thalamus, hippocampus and related glutamatergic neurotransmission pathways have been implicated in the pathophysiology of bipolar disorder. We have reviewed the existing literature over approximately two decades from 1990 to March 2008 for evidence that support structural, functional and chemical neuroimaging abnormalities as well as glutamatergic aberrations of the thalamus and the hippocampus in bipolar disorder. Available structural neuroimaging studies suggest a predominance of negative findings in terms of hippocampal and thalamic volumetric changes in bipolar disorder. Many functional neuroimaging studies however have found activation changes within the thalami, medial temporal lobes, prefrontal regions, and basal ganglia suggesting abnormal limbic-thalamo-cortical circuitry in bipolar disorder. The pattern of findings suggests abnormalities in the regulation of neuronal activity without fixed lesions in the thalamus or hippocampus. This could be related to factors such as cohort heterogeneity, image resolution and whether specific nuclei are examined, or that bipolar disorder is associated with greater neural inefficiency and greater reactivity to emotional stimuli. Chemical neuroimaging studies in bipolar disorder also implicate altered excitatory glutamate neurotransmission as well as cellular and membrane metabolism, especially pronounced within the hippocampus. Within the hippocampus, abnormalities of the ionotropic glutamate receptors were found in bipolar disorder with metabotropic glutamate receptors being relatively understudied. The few immunohistochemical studies performed on the thalamus also suggest the possibility of disturbances of glutamatergic neurotransmission involving intracellular signaling and trafficking processes in bipolar disorder. Overall, the emerging trends from these findings highlight the need for further research to unravel underlying neurobiological changes and clinical correlates of thalamic and hippocampal dysfunction in bipolar disorder.