Decreased Synaptic Connectivity

The cerebral cortex consists of six layers of neurons that have dense connections to each other, as well as to other neurons in different cortical and subcortical structures. The area between neurons (neuropil) consists of a dense network of dendrites, dendritic spines, axons, and axon terminals, which make connections between the neurons. In patients with schizophrenia, there are several lines of evidence indicating that there are fewer connections in the neocortex as well as the hippocampus.

Cerebral Cortex. In the cerebral cortex of patients with schizophrenia, concomitant with the increased cerebral ventricular space, there is a decrease in the thickness of the gray matter (Selemon et al., 1995; Selemon and Goldman-Rakic, 1999). Stereo-logical studies of the density of neurons in the prefrontal cortex have found that while the total number of neurons is not changed (Selemon, 2001), they are packed closer together (increased neuronal packing density). This indicates that the thinning of gray matter is due to a loss of neuropil, that is, the area between neurons that make up all the synaptic connections (see Fig. 9.3A and B).

As mentioned above, microarray studies have also revealed decreased expression of many genes involved in synaptic function (Mirnics et al., 2001). In addition, there is considerable evidence from scanning studies in live patients and histologi-cal studies in postmortem brains of schizophrenia patients consistent with this view. Measures of regional cerebral blood flow using positron emission tomography (PET) with fluorodeoxyglucose (FDG), which are in part measures of synaptic activity, reveal decreased metabolism in cortical areas as well as subcortical areas such as the striatum. Phosphorous magnetic resonance spectroscopy indicates a decrease in synaptogene-sis markers and an increase in markers of synaptic pruning. Immunocytochemical studies using markers of axon terminals [e.g., synaptophysin, y-aminobutyric acid (GABA), and GABA transporter (GAT)] found reductions in axon terminal density in the dorsal lateral prefrontal cortex (Glantz and Lewis, 1997; McGlashan and Hoffman, 2000; Selemon, 2001). Studies of Golgi-impregnated pyramidal neurons in the prefrontal cortex (Garey et al., 1998; Glantz and Lewis, 2000) reveal a reduction in the number of dendritic spines (see Fig. 9.3C-E). Dendritic spines are protrusions on den-drites that consequently provide more surface area to the dendrite, allowing for more synaptic contacts to be made. The striatum, a brain structure that receives substantial dopaminergic projections, a neurotransmitter heavily implicated in schizophrenia, also manifests smaller dendritic spines (see Fig. 9.3F and G) and alterations in synaptic density consistent with changes in several different pathways (Roberts et al., 1996; Kung et al., 1998).

Figure 9.3. Top panel: Photomicrographs taken at light microscopy of Nissl-stained coronal sections from the prefrontal cortex (area 9) of a normal brain (A) and the brain of a person with schizophrenia (B). Note that the cortex of the person with schizophrenia is thinner and has less intraneuronal neuropil than the normal control [Modified from Selemon et al. (1995). Reprinted by permission.] Middle panel: Photomicrographs taken at light microscopy of Golgi impregnated pyramidal neurons from layer III of the prefrontal cortex from the postmortem brains of a normal control subject (C) and two patients with schizophrenia (D and E). Note the decreased number of spines on the dendrites of pyramidal neurons in the schizophrenic patients [Modified from: Glantz and Lewis (2000). Reprinted with permission.] Bottom panel: Electron micrographs showing dendritic spines (sp) from the striatum of a normal control (F) and a person with schizophrenia (G). Note that spines are smaller in the striatum of the individual with schizophrenia (Roberts et al., 1995). For illustrative purposes, the difference in size is very pronounced. Synapses (white arrows), axon terminals (at), black arrows outline the spines.

Figure 9.3. Top panel: Photomicrographs taken at light microscopy of Nissl-stained coronal sections from the prefrontal cortex (area 9) of a normal brain (A) and the brain of a person with schizophrenia (B). Note that the cortex of the person with schizophrenia is thinner and has less intraneuronal neuropil than the normal control [Modified from Selemon et al. (1995). Reprinted by permission.] Middle panel: Photomicrographs taken at light microscopy of Golgi impregnated pyramidal neurons from layer III of the prefrontal cortex from the postmortem brains of a normal control subject (C) and two patients with schizophrenia (D and E). Note the decreased number of spines on the dendrites of pyramidal neurons in the schizophrenic patients [Modified from: Glantz and Lewis (2000). Reprinted with permission.] Bottom panel: Electron micrographs showing dendritic spines (sp) from the striatum of a normal control (F) and a person with schizophrenia (G). Note that spines are smaller in the striatum of the individual with schizophrenia (Roberts et al., 1995). For illustrative purposes, the difference in size is very pronounced. Synapses (white arrows), axon terminals (at), black arrows outline the spines.

Synaptic density is highest in childhood, with a 30 to 40 percent decline in adolescence following extensive pruning, settling in a relatively stable level in adulthood. It is noteworthy that the typical clinical onset of schizophrenia and the appearance of psychotic symptoms are coincident with the completion of the intense pruning that occurs in adolescence. Consistent with this, although highly speculative, computer simulation that models normal cognitive development and pruning, including the elimination of synaptic connections in the cortex, indicates that excessive pruning may lead to hallucinations, that is, speech perceptions that occur in the absence of stimulation (McGlashan and Hoffman, 2000).

Hippocampus. The hippocampus is a complex limbic structure that plays a role in emotion, cognition, memory, and inhibitory gating. Numerous studies from postmortem work to imaging of live patients implicate the hippocampus in schizophrenia. Postmortem findings indicate that the hippocampus is modestly reduced in size bilaterally. Reports of cell density in the hippocampus using classical counting techniques have shown a reduction in the density of neurons, but thus far these findings have yet to be replicated using more modern stereological techniques. Markers of axon terminals, such as synaptophysin, synapsin, and SNAP-25 are decreased in the hippocampus. Moreover, markers of dendrites such as MAP2 and MAP5 show decreased staining (Selemon, 2001). Taken together, these results suggest that reduced hippocampal size, like cortical thickness, may partially be the result of diminished neuropil volume, and hence a decrease in synaptic connectivity.

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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