Subnucleus-specific loss of neurons in medial thalamus of schizophrenics

Abstract

The hypoactivity of dorsolateral prefrontal cortex in schizophrenics is well known. One cause of this hypoactivity may be defective corticocortical or thalamocortical connections. Recent imaging studies of the thalamus suggest reductions in volume of the whole thalamus and reduced activity in the medial group of thalamic nuclei, which may indicate loss of functional input to the cortex. Using stereological techniques in six pairs of individually matched brains from schizophrenics and controls, we measured the volumes and obtained estimates of the number of neurons in the three subnuclei (parvocellular, pc; densocellular, dc; magnocellular, mc) of the mediodorsal nucleus (MD) and from the ventral posterior medial nucleus. There was a significant reduction in total neuron number in MD as a whole but this neuron loss was largely restricted to MDpc and MDdc [؊30.9 and ؊24.5%, respectively (P < 0.01)]. MDmc and the control ventral posterior medial nucleus showed no significant changes in cell number. Because the subnuclei of MD have different connections and project to different areas of the frontal cortex, the specific loss of neurons in MDpc and MDdc has implications for the functional defects observed in schizophrenia.mediodorsal nucleus ͉ prefrontal cortex ͉ hypoactivity ͉ stereology T he severe cognitive dysfunction of schizophrenia is associated with disturbances in activity of the dorsolateral prefrontal cortex (DLPFC) manifested by hypoactivity in imaging studies, deficiencies in tests of cognitive function, and putative, activity-dependent effects on gene expression for neurotransmitter-and receptor-related mRNAs. The causes of the functional disturbance frequently have been attributed to defective connectivity that could be both cortical and subcortical (1-4). The principal subcortical input to DLPFC arises in the mediodorsal nucleus (MD) of the thalamus, and recent imaging studies in schizophrenics have shown reductions in activity of the medial nuclei of the thalamus (5). Pakkenberg (6) had described earlier a reduction in the number of neurons in the MD of the thalamus in schizophrenics, but her figures for the control nuclei were only half of those reported for control nuclei in a later study (7), and Pakkenberg stated that her material was inadequate for accurately defining the borders of the large subnuclear divisions of the nucleus. Moreover, it was not stated whether neuronal loss was found in other thalamic nuclei as well.MD is composed of three major subnuclei: the magnocellular, parvocellular, and densocellular nuclei. The nuclei are delineated by cytoarchitecture and distinguished by major differences in cortical and subcortical connections (8-15). The magnocellular subnucleus (MDmc) occupies the anteromedial aspect of MD and is composed of relatively large, deeply stained neurons. MDmc is dominated by inputs from the olfactory and entorhinal cortices but also receives input from the amygdala; it projects to ventromedial and orbital cortex in the frontal lobe. The parvocellular nucleus (MDpc) oc...

Stereologic analysis of the lateral geniculate nucleus of the thalamus in normal and schizophrenic subjects

“…A number of studies indicate that heteromodal areas of the association cortex, including the prefrontal cortex, are key sites of pathology in the schizophrenic brain (Pearlson et al, 1996;Barch et al, 2001;Selemon, 2001). Thalamic nuclei that are reciprocally connected with heteromodal cortical areas have been shown to be smaller and have fewer neurons in schizophrenic subjects (Pakkenberg, 1990;Popken et al, 2000;Young et al, 2000;Byne et al, 2002;Danos et al, 2002;; however, our analysis suggests that the LGN does not exhibit comparable reductions in volume and neuronal number.…”

“…As reduction of thalamic volume and neuronal number has been described in several association nuclei of the thalamus, including the mediodorsal, anterior, pulvinar, and ventral lateral posterior nuclei (Pakkenberg, 1990;Popken et al, 2000;Young et al, 2000;Byne et al, 2002;Danos et al, 2002;, one possible explanation for the absence of cell loss in the LGN is that neuronal pathology in schizophrenia is restricted to nuclei with reciprocal connections to higher association cortices. It should be noted, however, that none of the postmortem studies that have described neuronal deficits in schizophrenic patients examined brains from the Stanley Foundation, the cohort that was analyzed in the present study.…”

“…In vivo neuroimaging studies of schizophrenic subjects have found smaller whole thalamic volume and altered thalamic shape (Ettinger et al, 2001;Gilbert et al, 2001;Csernansky et al, 2004), altered metabolic activity (Buchsbaum et al, 1996Hazlett et al, 1999 and reduction of volume in subregions or specific nuclei of the thalamus (Andreasen et al, 1994;Byne et al, 2001;Kemether et al, 2003). In addition, postmortem studies of brains from schizophrenic subjects have reported a reduction in total neuronal number and volume of individual thalamic nuclei, e.g., the mediodorsal, anterior, pulvinar and ventral lateral posterior nuclei (Pakkenberg, 1990;Popken et al, 2000;Young et al, 2000;Byne et al, 2002;Danos et al, 2002;. It should be noted, however, that several studies have not found evidence of thalamic pathology in schizophrenic subjects (Portas et al, 1998;Arciniegas et al, 1999;Deicken et al, 2002;Cullen et al, 2003;Dorph-Petersen et al, 2004;Preuss et al, 2005).…”

The Human Brain Revisited Opportunities and Challenges in Postmortem Studies of Psychiatric Disorders

“…However, the inference can be strengthened by comparing related measures between postmortem and in vivo imaging studies. For example, the likelihood that the reductions in volume and neuron number observed in the postmortem mediodorsal thalamus of subjects with schizophrenia (Pakkenberg 1990;Popken et al 2000;Young et al 2000) are related to the primary disease process is supported by the reported reductions in total thalamic volume (Buchsbaum et al 1996;Gur et al 1998;Gilbert et al 2001) and in the size of the mediodorsal nucleus (Byne et al 2001) in first-onset, never-medicated subjects with schizophrenia. A third strategy that has been less frequently utilized is the study of unaffected relatives of ill subjects.…”

“…For example, three published studies have found evidence of reduced numbers of glial cells in regions of the frontal cortex in subjects with depression (Ongur et al 1998;Rajkowska et al 1999;Cotter et al 2001). Within the field of schizophrenia research, three published studies have reported a similar ‫ف‬ 30% decrement in the number of neurons in the mediodorsal thalamic nucleus (Pakkenberg 1990;Popken et al 2000;Young et al 2000), two groups have found a reduction of somal size in deep layer 3 pyramidal neurons in prefrontal area 9 (Rajkowska et al 1998;Pierri et al 2001) and three independent research groups have found decreased expression of the mRNA for the 67 kilodalton isoform of glutamic acid decarboxylase (GAD 67 ), the synthesizing enzyme for GABA, in the dorsal prefrontal cortex (Akbarian et al 1995; Guidotti et al 2000;Volk et al 2000) of subjects with schizophrenia.Consequently, the opportunity for studies of the postmortem human brain to exploit rapidly developing technologies in the service of advancing our knowledge of psychiatric disorders has never been greater. However, as in any area of scientific investigation, such studies must be conducted with an adequate awareness of their strengths and limitations, and with appropriate attention to the types of issues that can maximize the strengths and mitigate the limitations.…”