RESUMO
2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Ketamina/administração & dosagem , Moléculas de Adesão de Célula Nervosa/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Córtex Pré-Frontal/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Deleção de Genes , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Tálamo/efeitos dos fármacosRESUMO
The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical circuits. Moreover, higher cognitive functions, such as working memory and attention, have been related to thalamo-cortical interactions, providing a novel perspective for the understanding of the neural substrate of cognition. The current review will support this perspective by summarizing evidence on the crucial role of neural oscillations in facilitating thalamo-cortical (TC) interactions during normal brain functioning and their potential impairment in ScZ. Specifically, we will focus on the relationship between NMDA-R mediated (glutamatergic) neurotransmission in TC-interactions. To this end, we will first review the functional anatomy and neurotransmitters in thalamic circuits, followed by a review of the oscillatory signatures and cognitive processes supported by TC-circuits. In the second part of the paper, data from preclinical research as well as human studies will be summarized that have implicated TC-interactions as a crucial target for NMDA-receptor hypofunctioning. Finally, we will compare these neural signatures with current evidence from ScZ-research, suggesting a potential overlap between alterations in TC-circuits as the result of NMDA-R deficits and stage-specific alterations in large-scale networks in ScZ.
Assuntos
Córtex Cerebral/fisiopatologia , Ácido Glutâmico/metabolismo , Esquizofrenia/fisiopatologia , Transmissão Sináptica/fisiologia , Tálamo/fisiopatologia , Animais , Ondas Encefálicas/fisiologia , Córtex Cerebral/patologia , Humanos , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/patologia , Tálamo/patologiaRESUMO
Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.