Aberrant cortical projections to amygdala GABAergic neurons contribute to developmental circuit dysfunction following early life stress

Haikonen, Joni; Englund, Jonas; Amarilla, Shyrley Paola; Kharybina, Zoia; Shintyapina, Alexandra; Kegler, Kristel; Garcia, Marta Saez; Atanasova, Tsvetomira; Taira, Tomi; Hartung, Henrike; Lauri, Sari E.

doi:10.1016/j.isci.2022.105724

Cited by 8 publications

(7 citation statements)

References 61 publications

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“…Consistently, ablation of GluK1 in PV+ neurons resulted in an increase in the strength of FFI at cortical inputs to LA principal neurons, confirming that PV+ neuron GluK1 receptors are necessary for balancing FFI in the LA. Furthermore, consistent with the critical role of FFI in gating LTP induction (Bissiere et al, 2003; Haikonen et al, 2023), LTP in the cortical inputs to BLA was significantly attenuated in PV- Grik1 -/- mice. Thus, while the some of the expected effects of PV+ neuron dysfunction on BLA circuit excitability appear to be developmentally compensated for, our data reveals an indispensable function for PV+ neuron GluK1 receptors in controlling the strength of FFI and consequently, threshold for LTP induction in the BLA.…”

Section: Discussionsupporting

confidence: 78%

“…Prolonged critical period plasticity involving excessive synaptic pruning could explain the reduced glutamatergic drive on to BLA neurons we observe in our knockout model. Interestingly, precocious maturation of PV+ neurons during early life stress is thought to drive premature closure of the critical period plasticity and result in significant alterations in cortico-amygdaloid connectivity across development (Guadagno et al, 2018; Honeycutt et al, 2020; Manzano Nieves et al, 2020; Haikonen et al, 2023). We have gathered some preliminary evidence via functional ultrasound imaging that medial prefrontal cortex (mPFC) to BLA resting state connectivity is impaired in PV- Grik1 -/- mice.…”

Section: Discussionmentioning

confidence: 99%

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GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

Haikonen,

Srinivasan,

Ojanen

et al. 2023

Preprint

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Parvalbumin expressing (PV+) interneurons are key players in the local inhibitory circuits and their developmental maturation coincides with the onset of adult-type network dynamics in the brain. Glutamatergic signaling regulates emergence of the unique PV+ neuron phenotype, yet the receptor mechanisms involved are not fully understood. Here we show that GluK1 subunit containing kainate receptors (KARs) are necessary for development and maintenance of the neurochemical and functional properties of PV+ interneurons in the basolateral amygdala (BLA). Ablation of GluK1 expression specifically from PV+ neurons resulted in low parvalbumin expression and loss of their characteristic high firing rate throughout development. In addition, we observed reduced spontaneous excitatory synaptic activity at adult GluK1 lacking PV+ neurons. Intriguingly, knockdown of GluK1 expression from adult PV+ neurons was sufficient to abolish the PV+ phenotype, suggesting a role for GluK1 in dynamic regulation of PV+ neuron maturation state. The PV+ neuron dysfunction in the absence of GluK1 perturbed feedforward inhibition and long-term potentiation (LTP) in the BLA and resulted in developmentally originating changes in the glutamatergic connectivity. Behaviorally, the absence of GluK1 from PV+ interneurons associated with hyperactivity and increased fear of novelty. These results indicate a critical role for GluK1 KARs in regulation of PV+ interneuron function across development and suggest GluK1 as a potential therapeutic target for pathologies involving PV+ neuron malfunction.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

Haikonen,

Srinivasan,

Ojanen

et al. 2023

Preprint

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“…In contrast to the anxiolytic effects of IL inputs to the amygdala, connections from the PL subregion are thought to drive fear expression (Pendyam et al, 2013;Marek et al, 2019) and promote anxiety (Kim et al, 2011) networks in vivo. These changes are sex-dependent, with the parameters detected in male but not female rats, who were also resistant to MS-dependent changes in anxiety-like behaviors (Haikonen et al, 2022).…”

Section: Pfc-amygdalamentioning

confidence: 93%

“…In contrast to the anxiolytic effects of IL inputs to the amygdala, connections from the PL subregion are thought to drive fear expression ( Pendyam et al, 2013 ; Marek et al, 2019 ) and promote anxiety ( Kim et al, 2011 ). Haikonen et al (2022) recently combined viral tracing and electrophysiological techniques to examine the effects of maternal separation (MS) on mPFC-to-BLA connectivity and function in young (P14-21) rats. Prolonged MS as an early-life stressor in young rodents is thought to induce emotional and behavioral abnormalities in adulthood, including increased anxiety-like behavior ( Kestering-Ferreira et al, 2021 ).…”

Section: Prefrontal Circuit-level Top-down Modulation Of Anxietymentioning

confidence: 99%

“…The enhanced GABAergic inhibition raises the induction threshold of long-term potentiation and associates with lower functional synchronization within prefrontal-amygdala networks in vivo . These changes are sex-dependent, with the parameters detected in male but not female rats, who were also resistant to MS-dependent changes in anxiety-like behaviors ( Haikonen et al, 2022 ).…”

Section: Prefrontal Circuit-level Top-down Modulation Of Anxietymentioning

confidence: 99%

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Prefrontal modulation of anxiety through a lens of noradrenergic signaling

Bouras

Mack

Gao

2023

Front. Syst. Neurosci.

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Anxiety disorders are the most common class of mental illness in the U.S., affecting 40 million individuals annually. Anxiety is an adaptive response to a stressful or unpredictable life event. Though evolutionarily thought to aid in survival, excess intensity or duration of anxiogenic response can lead to a plethora of adverse symptoms and cognitive dysfunction. A wealth of data has implicated the medial prefrontal cortex (mPFC) in the regulation of anxiety. Norepinephrine (NE) is a crucial neuromodulator of arousal and vigilance believed to be responsible for many of the symptoms of anxiety disorders. NE is synthesized in the locus coeruleus (LC), which sends major noradrenergic inputs to the mPFC. Given the unique properties of LC-mPFC connections and the heterogeneous subpopulation of prefrontal neurons known to be involved in regulating anxiety-like behaviors, NE likely modulates PFC function in a cell-type and circuit-specific manner. In working memory and stress response, NE follows an inverted-U model, where an overly high or low release of NE is associated with sub-optimal neural functioning. In contrast, based on current literature review of the individual contributions of NE and the PFC in anxiety disorders, we propose a model of NE level- and adrenergic receptor-dependent, circuit-specific NE-PFC modulation of anxiety disorders. Further, the advent of new techniques to measure NE in the PFC with unprecedented spatial and temporal resolution will significantly help us understand how NE modulates PFC function in anxiety disorders.

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Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats

Peart,

Nolan,

Stone

et al. 2024

Psychopharmacology

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Aberrant cortical projections to amygdala GABAergic neurons contribute to developmental circuit dysfunction following early life stress

Cited by 8 publications

References 61 publications

GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

Prefrontal modulation of anxiety through a lens of noradrenergic signaling

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats

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