1Curr. Mol. Med. 2015 -1 15: 237-44
TitleRegion-specific dendritic spine loss of pyramidal neurons in dopamine transporter knockout mice.
AbstractDopamine transporter (DAT) knockout (KO) mice show numerous behavioral alterations, including hyperlocomotion, cognitive deficits, impulsivity and impairment of prepulse inhibition of the startle reflex (PPI), phenotypes that may be relevant to frontostriatal disorders such as schizophrenia. Dendritic spine changes of pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) are among the most replicated of findings in postmortem studies of schizophrenia. The mechanisms that account for dendritic changes in the DLPFC in schizophrenia are unclear. Here, we report basal spine density of pyramidal neurons in the medial prefrontal cortex (mPFC), the motor cortex, the CA1 region of the hippocampus, and the basolateral amygdala in DAT KO mice. Pyramidal neurons were visualized using DAT KO mice crossbred with a THY1-GFP transgenic mouse line. We observed a significant decrease in spine density of pyramidal neurons in the mPFC and the CA1 region of the hippocampus in DAT KO mice compared to that in WT mice. On the other hand, no difference was observed in spine density of pyramidal neurons in the motor cortex or the basolateral amygdala between DAT genotypes. These results suggest that decreased spine density could cause hypofunction of the mPFC and the hippocampus, and contribute to the behavioral abnormalities observed in DAT KO mice, including cognitive deficits. This might suggest that aberrant dopaminergic signaling may trigger dystrophic changes in dendrites of hippocampal and prefrontocortical pyramidal neurons in schizophrenia.
SCZ Keywordsschizophrenia
2Front Neural Circuits 2015 -1 9: 5
TitleAdolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent.
AbstractThe maturation of inhibitory circuits during adolescence may be tied to the onset of mental health disorders such as schizophrenia. Neurotrophin signaling likely plays a critical role in supporting inhibitory circuit development and is also implicated in psychiatric disease. Within the neocortex, subcircuits may mature at different times and show differential sensitivity to neurotrophin signaling. We measured miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs) in Layer 5 cell-types in the mouse anterior cingulate (Cg) across the periadolescent period. We differentiated cell-types mainly by THY1 YFP transgene expression and also retrobead injection labeling in the contralateral Cg and ipsilateral pons. We found that YFP- neurons and commissural projecting neurons had lower frequency of mIPSCs than neighboring YFP+ neurons or pons projecting neurons in juvenile mice (P21-25). YFP- neurons and to a lesser extent commissural projecting neurons also showed a significant increase in mIPSC amplitude during the periadolescent period (P21-25 vs. P40-50), which was not seen in YFP+ neurons or pons projecting neurons. Systemic disruption of tyrosine kinase receptor B (TrkB) signaling during P23-50 in TrkBF616A mice blocked developmental changes in mIPSC amplitude, without affecting miniature excitatory post synaptic currents (mEPSCs). Our data suggest that the maturation of inhibitory inputs onto Layer 5 pyramidal neurons is cell-type specific. These data may inform our understanding of adolescent brain development across species and aid in identifying candidate subcircuits that may show greater vulnerability in mental illness.
SCZ Keywordsschizophrenia