Calcium binding protein markers of GABA deficits in schizophrenia — post mortem studies and animal models

Abstract

As quantitative neuroimaging continues to elucidate the gross neuropathology of schizophrenia, neurochemical and histological studies have contributed to defining this pathology in terms of neurotransmitter dysfunction. Increasingly, there is evidence implicating neurons containing the major inhibitory neurotransmitter of the brain--gamma-aminobutyric acid (GABA). Benes was the first to demonstrate deficits in some morphological subtypes of interneurons in the frontal cortex in schizophrenia. We identified that this was specific to a subgroup of GABAergic interneurons containing parvalbumin (PV), which is found in the fast-firing cells providing inhibitory control of the cortico-fugal pyramidal cells. PV is notable in being expressed late in development; the late expression of this protective calcium binding protein (CBP) may impart an early vulnerability to these neurons, indicating a possible mechanism for the developmental origins of schizophrenia. Cortical GABAergic neurons expressing the CBP calretinin (CR) are unaffected in schizophrenia, although those containing calbindin (CB) are also diminished in number. These deficits in PV and CB are notable in also being observed in bipolar disorder, indicating how the close aetiological relationship of these two psychiatric disorders is reflected in their pathology. One of the most substantial abnormalities seen in post-mortem brain tissue is the hippocampal deficit of PV-containing neurons, again in the absence of effects on CR-positive cells. This deficit occurring in a structure implicated in cognitive symptomatology may well have functional relevance, and we find it can be induced by a model of the disease, sub-chronic phencyclidine (PCP) administration, that can also produce cognitive disturbances. This PCP model, like schizophrenia, demonstrates other neurochemical changes which include indicators of glutamatergic dysfunction. The temporal and aetiological relationships between glutamatergic and GABAergic deficits remains unclear, but may well relate to an initial loss/dysfunction of GABA/PV neurons that subsequently gives rise to a glutamatergic pathology.

Differences in locomotor behavior revealed in mice deficient for the calcium-binding proteins parvalbumin, calbindin D-28k or both

“…Moreover, reduced immunoreactivity for PV and/or CB was reported in surviving cerebellar Purkinje cells [21] of patients with spinocerebellar ataxia-1 (SCA-1) and in an animal model using SCA-1 transgenic mice [22]. Decreases in PV expression were one of the most consistent findings in postmortem brains of patients with schizophrenia, bipolar disorder and major depression [23] and also downregulation of CB expression was reported before [24]. The results obtained in human patients and genetically modified mice clearly indicate that the presence or absence of PV or CB has significant effects on synaptic transmission and are likely to have profound effects at the systemic level including behavior, learning or memory.…”

Calbindin D28k targets myo -inositol monophosphatase in spines and dendrites of cerebellar Purkinje neurons

“…21). Interestingly, postmortem studies of bipolar disease patients revealed a loss of CB immunoreactivity in the CNS (39). Furthermore, a form of inherited bipolar disease is associated with ataxia (40), and cerebellar ataxia is a common sign of Li ϩ overdosing in the treatment of bipolar disease (41)(42)(43).…”

Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

“…Accordingly, rodents and nonhuman primates treated with non-competitive NMDAR antagonists display behavioral features consistent with many symptoms of schizophrenia . Repeated dosing with these drugs may provide greater validity than acute administration, as such regimens induce neurochemical changes similar to those seen in schizophrenic patients (Cochran et al, 2003;Enomoto et al, 2005;Reynolds et al, 2004), as well as lasting cognitive deficits that can be observed when animals are tested in a drug-free state (Jentsch and Roth, 1999).…”