Dataset Information

Inhibition of 14-3-3 Proteins Alters Neural Oscillations in Mice.

ABSTRACT: Accumulating evidence suggests that schizophrenia is a disorder of the brain's communication, a result of functional and structural dysconnectivities. Patients with schizophrenia exhibit irregular neuronal circuit and network activity, but the causes and consequences of such activity remain largely unknown. Inhibition of 14-3-3 proteins in the mouse brain leads to the expression of multiple schizophrenia endophenotypes. Here we investigated how 14-3-3 inhibition alters neuronal network activity in the mouse hippocampus (HPC) and prefrontal cortex (PFC), key brain regions implicated in schizophrenia pathophysiology. We implanted monopolar recording electrodes in these two regions to record local field potentials both at rest and during a cognitive task. Through our assessment of band power, coherence, and phase-amplitude coupling, we found that neural oscillations in the theta and gamma frequency ranges were altered as a result of 14-3-3 dysfunction. Utilizing transgenic and viral mouse models to assess the effects of chronic and acute 14-3-3 inhibition on oscillatory activities, respectively, we observed several fundamental similarities and differences between the two models. We localized viral mediated 14-3-3 protein inhibition to either the HPC or PFC, allowing us to assess the individual contributions of each region to the observed changes in neural oscillations. These findings identify a novel role of 14-3-3 proteins in neural oscillations that may have implications for our understanding of schizophrenia neurobiology.

SUBMITTER: Jones ZB

PROVIDER: S-EPMC7994333 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Inhibition of 14-3-3 Proteins Alters Neural Oscillations in Mice.

Jones Zachary B ZB Zhang Jiajing J Wu Yuying Y Zhou Yi Y

Frontiers in neural circuits 20210312

Accumulating evidence suggests that schizophrenia is a disorder of the brain's communication, a result of functional and structural dysconnectivities. Patients with schizophrenia exhibit irregular neuronal circuit and network activity, but the causes and consequences of such activity remain largely unknown. Inhibition of 14-3-3 proteins in the mouse brain leads to the expression of multiple schizophrenia endophenotypes. Here we investigated how 14-3-3 inhibition alters neuronal network activity ...[more]

PMID: 33776658

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Project description:Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABA(A,fast) and GABA(A,slow). In hippocampal area CA1, GABA(A,fast) is generally believed to underlie gamma oscillations, whereas the contribution of GABA(A,slow) to hippocampal rhythms has been speculative. Hypothesizing that GABA(A) receptors containing the beta(3) subunit contribute to GABA(A,slow) inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABA(A) receptor beta(3) subunit-deficient (beta(3)(-/-)) mice, spontaneous GABA(A,slow) inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABA(A,slow) currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing beta(3) subunits contribute substantially to GABA(A,slow) currents in pyramidal neurons. By contrast, slow inhibitory control of GABA(A,fast)-producing interneurons was unaffected in beta(3)(-/-) mice. In vivo hippocampal network activity was markedly different in the two genotypes. In beta(3)(-/-) mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency ("nesting") was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of beta(3) subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABA(A,fast) -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

Dataset Information

Inhibition of 14-3-3 Proteins Alters Neural Oscillations in Mice.

Publications

Inhibition of 14-3-3 Proteins Alters Neural Oscillations in Mice.

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