Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia

“Edges of PV+ or CR+ cell bodies were segmented by the MATLAB edge function using the Canny edge detector operator(30).”

“Because cortical gamma oscillations require the activity of parvalbumin-containing (PV) interneurons(4, 5), deficient cortical PV interneuron activity could provide the neural substrate for altered prefrontal gamma oscillations and consequently impaired working memory in schizophrenia.”

“Because cortical gamma oscillations require the activity of parvalbumin-containing (PV) interneurons(4, 5), deficient cortical PV interneuron activity could provide the neural substrate for altered prefrontal gamma oscillations and consequently impaired working memory in schizophrenia.”

“Excitatory synapses on PV interneurons predict PV and GAD67 expression levels in human DLPFC Finally, we assessed whether the density of excitatory synapses on PV+ neurons predicted levels of PV and GAD67, molecular markers of PV interneuron activity.”

“First, we did not sample vesicular glutamate transporter 2-containing excitatory inputs that represent projections from the thalamus(40).”

“Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19).”

“These deficits do not seem to be due to a global reduction in excitatory drive to all interneuron subtypes, as calretinin-containing (CR) interneurons, the most abundant interneuron subtype in the primate DLPFC(20), appear to be relatively unaffected in schizophrenia(15, 16, 21).”

“Cognitive dysfunction is a core and clinically-critical feature of schizophrenia(1) but responds poorly to available medications(2).”

“, PV and the GABA-synthesizing enzyme glutamic acid decarboxylase 67, GAD67), abnormal gamma oscillations and working memory deficits(9-12).”

“VGlut1+ and PSD95+ puncta were used to identify the pre- and postsynaptic elements, respectively, as these molecular markers have been previously used to define excitatory synapses in PV interneurons(11, 28, 29).”

“Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19).”

“, PV and the GABA-synthesizing enzyme glutamic acid decarboxylase 67, GAD67), abnormal gamma oscillations and working memory deficits(9-12).”

“Excitatory synapses on PV interneurons predict PV and GAD67 expression levels in human DLPFC Finally, we assessed whether the density of excitatory synapses on PV+ neurons predicted levels of PV and GAD67, molecular markers of PV interneuron activity.”

“Lower glutamatergic drive to PV interneurons has been hypothesized to be the cause of deficient PV interneuron activity in schizophrenia(6-8).”

“Trough plasma levels for haloperidol and olanzapine were within the range associated with clinical efficacy in humans(31).”

“These deficits do not seem to be due to a global reduction in excitatory drive to all interneuron subtypes, as calretinin-containing (CR) interneurons, the most abundant interneuron subtype in the primate DLPFC(20), appear to be relatively unaffected in schizophrenia(15, 16, 21).”

“For example, the ErbB4 signaling pathway induces the formation of excitatory synapses on PV interneurons(11, 43, 44) and the release of neuronal pentraxin 2 (Narp) from pyramidal cells recruits excitatory synapses selectively on PV interneurons in an activitydependent manner(28).”

“For example, the ErbB4 signaling pathway induces the formation of excitatory synapses on PV interneurons(11, 43, 44) and the release of neuronal pentraxin 2 (Narp) from pyramidal cells recruits excitatory synapses selectively on PV interneurons in an activitydependent manner(28).”

“Layer 2 or 4 was defined as 10-20% or 50-60% of the piato-white matter distance, respectively(25).”

“25 μm z-step) in layer 2 or 4 from each section were selected using a previously published method for systematic random sampling(24).”

“Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19).”

“, PV and the GABA-synthesizing enzyme glutamic acid decarboxylase 67, GAD67), abnormal gamma oscillations and working memory deficits(9-12).”

“Lower glutamatergic drive to PV interneurons has been hypothesized to be the cause of deficient PV interneuron activity in schizophrenia(6-8).”

“Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19).”

“For example, the ErbB4 signaling pathway induces the formation of excitatory synapses on PV interneurons(11, 43, 44) and the release of neuronal pentraxin 2 (Narp) from pyramidal cells recruits excitatory synapses selectively on PV interneurons in an activitydependent manner(28).”

“Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19).”

“Excitatory synapses on PV interneurons predict PV and GAD67 expression levels in human DLPFC Finally, we assessed whether the density of excitatory synapses on PV+ neurons predicted levels of PV and GAD67, molecular markers of PV interneuron activity.”

“Lower glutamatergic drive to PV interneurons has been hypothesized to be the cause of deficient PV interneuron activity in schizophrenia(6-8).”

“In addition, to control for the autofluorescence emitted by lipofuscin which accumulates with aging(22), all subjects were less than 62 years of age.”

“Paraformaldehyde-fixed coronal tissue sections (40μm) containing DLPFC area 9 were processed for fluorescent immunohistochemistry as previously described(23).”

“PV interneurons comprise two main subtypes: PV basket neurons target the proximal dendrites and cell bodies of pyramidal neurons and PV chandelier neurons synapse onto the axon initial segment of pyramidal neurons(35).”

“Excitatory synapses on PV interneurons predict PV and GAD67 expression levels in human DLPFC Finally, we assessed whether the density of excitatory synapses on PV+ neurons predicted levels of PV and GAD67, molecular markers of PV interneuron activity.”

“Although both populations of PV interneuron subtypes are active during gamma oscillations, gamma rhythms are more strongly coupled to the activity of PV basket neurons(36, 37).”

“Experimental reductions of GAD67 in PV interneurons decrease inhibitory synaptic transmission in pyramidal cells and alter cortical network activity(48-50).”

“Experimental reductions of GAD67 in PV interneurons decrease inhibitory synaptic transmission in pyramidal cells and alter cortical network activity(48-50).”

“Although the density of excitatory synapses is higher onto dendrites than cell bodies of PV interneurons(30), depolarization of the cell body of PV interneurons is much stronger for somal than dendritic excitatory inputs(31,32).”

“Although both populations of PV interneuron subtypes are active during gamma oscillations, gamma rhythms are more strongly coupled to the activity of PV basket neurons(36, 37).”

“These deficits do not seem to be due to a global reduction in excitatory drive to all interneuron subtypes, as calretinin-containing (CR) interneurons, the most abundant interneuron subtype in the primate DLPFC(20), appear to be relatively unaffected in schizophrenia(15, 16, 21).”

“Excitatory synapses on PV interneurons predict PV and GAD67 expression levels in human DLPFC Finally, we assessed whether the density of excitatory synapses on PV+ neurons predicted levels of PV and GAD67, molecular markers of PV interneuron activity.”

“However, thalamic axons represent a small minority (<10%) of excitatory terminals in the cortex(41) and only a small percentage of thalamic inputs target PV interneurons(42), suggesting that the excitation of PV interneurons is mostly driven by cortical excitatory inputs.”

“Both an abnormal shift in ErbB4 splicing at the JM locus(45, 46) and lower Narp transcript levels have been shown in the DLPFC of subjects with schizophrenia, including those included in the present study(21, 47).”

“Lipofuscin for each stack was imaged using a custom fifth channel (excitation wavelength: 405nm; emission wavelength: 647nm) at a constant exposure time as previously described(27).”

“Both an abnormal shift in ErbB4 splicing at the JM locus(45, 46) and lower Narp transcript levels have been shown in the DLPFC of subjects with schizophrenia, including those included in the present study(21, 47).”

“Pearson’s correlation analysis was performed to assess the relationships between the density of VGlut1+/PSD95+ puncta on PV+ cell bodies and somal PV immunoreactivity levels or PV and GAD67 mRNA levels obtained from previously published studies(32, 33).”

“Furthermore, findings of altered ErbB4 splicing [189], and an associated deficit in the density of excitatory inputs onto PV neurons [159], suggest the possibility of a primary pathological process in PV neurons.”

“Furthermore, individuals with schizophrenia have a lower density of excitatory synapses on PV-INs [12] and exhibit alterations in gamma oscillations during a working memory task [13].”

“Recent data suggest that deficits in GABA neuronal function associated with schizophrenia arise as a consequence of deficient excitatory input (53) or responsivity to this input (54) and serve to reduce inhibition in cortical microcircuits in ways that compensate for reduced excitatory connectivity (55).”