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Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood.

ABSTRACT: In genetic and pharmacological models of neurodevelopmental disorders, and human data, neural activity is altered within the developing neocortical network. This commonality begs the question of whether early enhancement in excitation might be a common driver, across etiologies, of characteristic behaviors. We tested this concept by chemogenetically driving cortical pyramidal neurons during postnatal days 4-14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expressing neurons, led to decreased social interaction and increased grooming activity in adult animals. In vivo optogenetic interrogation in adults revealed decreased baseline but increased stimulus-evoked firing rates of pyramidal neurons and impaired recruitment of inhibitory neurons. Slice recordings in adults from prefrontal cortex layer 5 pyramidal neurons revealed decreased intrinsic excitability and increased synaptic E/I ratio. Together these results support the prediction that enhanced pyramidal firing during development, in otherwise normal cortex, can selectively drive altered adult circuit function and maladaptive changes in behavior.

SUBMITTER: Medendorp WE

PROVIDER: S-EPMC7907816 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood.

Medendorp William E WE Bjorefeldt Andreas A Crespo Emmanuel L EL Prakash Mansi M Pal Akash A Waddell Madison L ML Moore Christopher I CI Hochgeschwender Ute U

iScience 20210207 3

In genetic and pharmacological models of neurodevelopmental disorders, and human data, neural activity is altered within the developing neocortical network. This commonality begs the question of whether early enhancement in excitation might be a common driver, across etiologies, of characteristic behaviors. We tested this concept by chemogenetically driving cortical pyramidal neurons during postnatal days 4-14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expr ...[more]

PMID: 33665575

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Project description:BACKGROUND:Interferon-? (IFN-?, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-? modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-? (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-?. METHODS:We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-? receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-?. RESULTS:We show that IFN-? receptors are present in the membrane of rat's neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-? diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-? did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-?. Indeed, IFN-? increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-?, whereas their frequency remained unchanged. CONCLUSIONS:The expression of IFN-? receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-? highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-? in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.

Dataset Information

Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood.

Publications

Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood.

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