Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia

Schizophrenia is a debilitating psychiatric disorder characterized by positive, negative and cognitive symptoms. Despite more than a century of research, the neurobiological mechanism underlying schizophrenia remains elusive. White matter abnormalities and interneuron dysfunction are the most widely replicated cellular neuropathological alterations in patients with schizophrenia. However, a unifying model incorporating these findings has not yet been established. Here, we propose that myelination of fast-spiking parvalbumin (PV) interneurons could be an important locus of pathophysiological convergence in schizophrenia. Myelination of interneurons has been demonstrated across a wide diversity of brain regions and appears highly specific for the PV interneuron subclass. Given the critical influence of fast-spiking PV interneurons for mediating oscillations in the gamma frequency range (~30–120 Hz), PV myelination is well positioned to optimize action potential fidelity and metabolic homeostasis. We discuss this hypothesis with consideration of data from human postmortem studies, in vivo brain imaging and electrophysiology, and molecular genetics, as well as fundamental and translational studies in rodent models. Together, the parvalbumin interneuron myelination hypothesis provides a falsifiable model for guiding future studies of schizophrenia pathophysiology.Molecular Psychiatry advance online publication, 20 September 2016; doi:10.1038/mp.2016.147

On the Myelination of GABAergic Interneurons

Myelination is the insulating ensheathment of axons by oligodendrocytes to increase action potential propagation and provide metabolic support. GABAergic interneurons are a heterogeneous group of predominantly local, inhibitory cells. In schizophrenia, a major debilitating psychiatric disorder, both myelination as well as functioning of GABAergic interneurons have independently been suggested to be impaired. Whether GABAergic interneurons themselves show myelination, remains unknown. Here, we show that GABAergic myelination has been extensiv

Fast-spiking Parvalbumin Interneurons are Frequently Myelinated in the Cerebral Cortex of Mice and Humans

Myelination, the insulating ensheathment of axons by oligodendrocytes, is thought to both optimize signal propagation and provide metabolic support. Despite the well-established physiological importance of myelination to neuronal function, relatively little is known about the myelination of GABAergic interneurons in the cerebral cortex. Here, we report that a large fraction of myelin in mouse cerebral cortex ensheaths GABAergic interneurons, reaching up to 80% in hippocampal subregions. Moreover, we find that a very high proportion of neocortical and hippocampal parvalbumin (PV) interneurons exhibit axonal myelination. Using a combination of intracellular recordings and biocytin labeling of ex vivo human neocortex, we also confirm that axons of fast-spiking PV interneurons are extensively myelinated in the human brain. PV interneuron myelination in both mice and humans exhibits a stereotyped topography with a bias towards proximal axonal segments and relatively short internodes (∼27 μm) interspersed with branch points. Interestingly, myelin-deficient Shiverer mice exhibit an increased density and more proximal location of en passant boutons, suggesting that myelination might function in part to regu

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments

Social identity modifies face perception: an ERP study of social categorization

Two studies examined whether social identity processes, i.e. group identification and social identity threat, amplify the degree to which people attend to social category information in early perception [assessed with event-related brain potentials (ERPs)]. Participants were presented with faces of Muslims and non-Muslims in an evaluative priming task while ERPs were measured and implicit evaluative bias was assessed. Study 1 revealed that non-Muslims showed stronger differentiation between ingroup and outgroup faces in both early (N200) and later processing stages (implicit evaluations) when they identified more strongly with their ethnic group. Moreover, identification effects on implicit bias were mediated by intergroup differentiation in the N200. In Study 2, social identity threat (vs control) was manipulated among Muslims. Results revealed that high social identity threat resulted in stronger differentiation of Muslims from non-Muslims in early (N200) and late (implicit evaluations) processing stages, with N200 effects again predicting implicit bias. Combined, these studies reveal how seemingly bottom-up early social categorization processes are affected by individual and contextual variables that affect the meaning of social identity. Implications of these results for the social identity perspective as well as social cognitive theories of person perception are discussed

Social identity modifies face perception: an ERP study of social categorization

Two studies examined whether social identity processes, i.e. group identification and social identity threat, amplify the degree to which people attend to social category information in early perception [assessed with event-related brain potentials (ERPs)]. Participants were presented with faces of Muslims and non-Muslims in an evaluative priming task while ERPs were measured and implicit evaluative bias was assessed. Study 1 revealed that non-Muslims showed stronger differentiation between ingroup and outgroup faces in both early (N200) and later processing stages (implicit evaluations) when they identified more strongly with their ethnic group. Moreover, identification effects on implicit bias were mediated by intergroup differentiation in the N200. In Study 2, social identity threat (vs control) was manipulated among Muslims. Results revealed that high social identity threat resulted in stronger differentiation of Muslims from non-Muslims in early (N200) and late (implicit evaluations) processing stages, with N200 effects again predicting implicit bias. Combined, these studies reveal how seemingly bottom-up early social categorization processes are affected by individual and contextual variables that affect the meaning of social identity. Implications of these results for the social identity perspective as well as social cognitive theories of person perception are discussed

Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice

Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD