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1.
Genes Brain Behav ; 17(6): e12466, 2018 07.
Article in English | MEDLINE | ID: mdl-29446202

ABSTRACT

Inhibitory interneurons mediate the gating of synaptic transmission and modulate the activities of neural circuits. Disruption of the function of inhibitory networks in the forebrain is linked to impairment of social and cognitive behaviors, but the involvement of inhibitory interneurons in the cerebellum has not been assessed. We found that Cadherin 13 (Cdh13), a gene implicated in autism spectrum disorder and attention-deficit hyperactivity disorder, is specifically expressed in Golgi cells within the cerebellar cortex. To assess the function of Cdh13 and utilize the manipulation of Cdh13 expression in Golgi cells as an entry point to examine cerebellar-mediated function, we generated mice carrying Cdh13-floxed alleles and conditionally deleted Cdh13 with GlyT2::Cre mice. Loss of Cdh13 results in a decrease in the expression/localization of GAD67 and reduces spontaneous inhibitory postsynaptic current (IPSC) in cerebellar Golgi cells without disrupting spontaneous excitatory postsynaptic current (EPSC). At the behavioral level, loss of Cdh13 in the cerebellum, piriform cortex and endopiriform claustrum have no impact on gross motor coordination or general locomotor behaviors, but leads to deficits in cognitive and social abilities. Mice lacking Cdh13 exhibit reduced cognitive flexibility and loss of preference for contact region concomitant with increased reciprocal social interactions. Together, our findings show that Cdh13 is critical for inhibitory function of Golgi cells, and that GlyT2::Cre-mediated deletion of Cdh13 in non-executive centers of the brain, such as the cerebellum, may contribute to cognitive and social behavioral deficits linked to neurological disorders.


Subject(s)
Cadherins/deficiency , Cerebellum/physiology , Cognition/physiology , Golgi Apparatus/physiology , Animals , Cadherins/genetics , Cadherins/metabolism , Cerebellum/metabolism , Female , GABAergic Neurons/metabolism , Gene Expression Profiling , Golgi Apparatus/genetics , Golgi Apparatus/metabolism , Interneurons/metabolism , Male , Mice , Social Behavior , Synaptic Transmission , gamma-Aminobutyric Acid/metabolism
2.
Mol Psychiatry ; 19(10): 1143-9, 2014 Oct.
Article in English | MEDLINE | ID: mdl-23999527

ABSTRACT

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.


Subject(s)
Autoantibodies/blood , Blood-Brain Barrier/metabolism , Mood Disorders/metabolism , Parkinson Disease/metabolism , Receptors, N-Methyl-D-Aspartate/immunology , Schizophrenia/metabolism , Adult , Aged , Animals , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Cerebral Cortex/metabolism , Endocytosis/physiology , Female , Genome-Wide Association Study , Humans , Influenza, Human/genetics , Influenza, Human/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mood Disorders/genetics , Neurons/metabolism , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Receptors, N-Methyl-D-Aspartate/genetics , Schizophrenia/genetics
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