Dendrite Plasticity in the Thalamus and Prefrontal Cortex: Relevance to Schizophrenia
Description
Schizophrenia is a debilitating neurological disorder affecting 1% of people. While the causes remain unknown, evidence demonstrates both developmental and anatomical origins of the disorder. Reduced volume and neuropil in the prefrontal cortex (PFC) and mediodorsal (MD) the thalamus is found in schizophrenics, possibly through loss of dendrite complexity and volume. Many symptoms of schizophrenia are linked to the function of these structures. Reduced dendritic arborization may result in abnormal neurotransmission, as dendritic complexity determines information processing capabilities of a neuron. The studies presented here explore the role of dendrite plasticity in the PFC and MD thalamus. Antipsychotic treatment may restore volume in affected brain regions. Our data show that chronic treatment with the atypical antipsychotic, clozapine, which treats more symptoms of schizophrenia, increases dendritic complexity and length in the MD thalamus, whereas haloperidol, a typical antipsychotic, had no effect. Both drugs had affected dendrite morphology in the PFC, although in different patterns. This suggests that symptom improvement and volume restoration may be due to changes in dendritic architecture. Protein levels of factors related to synaptic plasticity and dendrite morphology were examined in these areas following treatment. This study found that clozapine may increase surface expression of glutamate receptors in the PFC and increases dendritic spines in the thalamus, implying increased synaptic connectivity. However, a putative mechanism was not revealed. The direct actions of these drugs on cortical and thalamic neurons were tested in vitro to further elucidate their actions. The changes in dendrite morphology found in this model differed from what was found in vivo, suggesting antipsychotic drugs act at a circuit level. A developmental glutamate hypofunction model of schizophrenia, based on evidence of glutamate disruption in schizophrenia, was examined and compared to known abnormalities in schizophrenia. This study revealed evidence of impaired synaptic pruning in the thalamus following glutamate hypofunction. However, the changes were not representative of known changes in schizophrenia, suggesting this treatment protocol does not generate a representative model of schizophrenia. The findings presented here better define the role of dendrite morphology in the corticothalamic circuit with regards to the treatment and pathology of schizophrenia