Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model

Abstract

Alteration in normal hippocampal (HPC) function attributed to reduced parvalbumin (PV) expression has been consistently reported in schizophrenia patients and in animal models of schizophrenia. However, it is unclear whether there is an overall loss of interneurons as opposed to a reduction in activity-dependent PV content. Co-expression of PV and the constitutively-expressed substance P (SP)-receptor protein has been utilized in other models to ascertain the degree of cell survival, as opposed to reduction in activity-dependent PV content, in the HPC. The present study measured the co-expression of PV and SP-receptors in the dentate and dorsal and ventral CA3 subregions of the HPC in the methylazoymethanol acetate (MAM) rat neurodevelopmental model of schizophrenia. In addition, these changes were compared at the postnatal day 27 (PND27) and post-natal day 240 (PND240) time points. Brains from PND27 and PND240 MAM (n=8) and saline (SAL, n=8) treated offspring were immunohistochemically processed for the co-expression of PV and SP-receptors. The dorsal dentate, dorsal CA3 and ventral CA3 subregions of PND27 and PND>240 MAM rats demonstrated significant reductions in PV but not SP-receptor expression, signifying a loss of PV-content. In contrast, in the ventral dentate the co-expression of PV and SP-receptors was significantly reduced only in PND>240 MAM animals, suggesting a reduction in cell number. While MAM-induced reduction of PV content occurs in CA3 of dorsal and ventral HPC, the most substantial loss of interneuron number is localized to the ventral dentate of PND>240 animals. The disparate loss of PV in HPC subregions likely impacts intra-HPC network activity in MAM rats.

Amygdala Hyperactivity in MAM Model of Schizophrenia is Normalized by Peripubertal Diazepam Administration

“…Similarly, in our MAM-treated rats, the hyperlocomotion in response to psychostimulants is only observed in adults but not in younger rats (Moore et al, 2006). However, at juvenile and peripubertal ages, these MAM rats already exhibit a significant degree of pathology: they are more sensitive to stress and more anxious (Du and Grace, 2013;Zimmerman et al, 2013), and the reduction of parvalbumin expression in the hippocampus initiates in juvenile MAM rats (Chen et al, 2014;Gill and Grace, 2014).…”

“…For example, parvalbumin interneurons are sensitive to stress (Czeh et al, 2005;Hu et al, 2010) and would likely be affected. And indeed, the loss of parvalbumin interneurons in the hippocampus initiated in juvenile rats and progressed into adulthood (Gill and Grace, 2014). Loss of parvalbumin in the hippocampus is related to anxiety behaviors (Quarta et al, 2015).…”

Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model

“…vSub inactivation completely abolished elevated DA population activity in MAM rats, thereby establishing a causal link between excessive hippocampal activity and DA system hyper-responsivity in MAM rats. Like schizophrenia patients, MAM animals also exhibit a reduction in PV-expressing interneurons within the vSub and PFC and display deficits in gamma oscillatory activity (Gill and Grace, 2014; Lodge et al, 2009). En masse, these data indicate that a loss of PV interneuron function in the vSub results in alterations in vSub output that drives a hyper-responsive DA system that underlies the positive symptoms of schizophrenia (Grace, submitted).…”

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

“…106 Moreover, evidence in patients 33 and in MAM rats suggest that in the PFC there is a general decrease in PV levels rather than PVI loss, whereas in hippocampus it appears that neuronal loss occurs. 107 Third, genetic models (eg, DISC1, PRODH, G71) all exhibit elevated oxidative stress consistent with their PVI abnormalities. In addition, preliminary results in collaboration with the Coyle and La Mantia labs, respectively, reveal oxidative stress-induced PVI/PNN loss in d-serine racemase KO and 22q11 mouse models (K. Q.…”