Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration

Chamberlin, Linda A.; Yang, Sha-Sha; McEachern, Erin; Lucas, Joshua; McLeod, Owen W; Rolland, Claire A; Mack, Nancy R.; Ferguson, Brielle R.; Gao, Wen-Jun

doi:10.1038/s41386-023-01576-6

Cited by 11 publications

(3 citation statements)

References 70 publications

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“…It is plausible that attenuated excitability of pyramidal cells mimicked the control of PV INs on pyramidal cells and thus led to positive outcomes on cognitive behavior. In support of this, chemogenetic activation of PV interneurons was found to reverse cognitive deficits induced by adolescent MK-801 (Chamberlin et al, 2023; Huang et al, 2021). Hence, both reduced excitation and increased inhibition might lead to beneficial outcomes on cognitive impairments.…”

Section: Discussionmentioning

confidence: 64%

Chemogenetic attenuation of PFC pyramidal neurons restores deficits in recognition memory following adolescent NMDA receptor blockade

Bauminger,

Chandran,

Akirav

et al. 2024

Preprint

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During adolescence, the prefrontal cortex (PFC) undergoes dramatic developmental changes, including fine-tuning the balance between excitatory glutamate and inhibitory GABA transmission (i.e., the E/I balance). This process is critical for intact cognitive function and social behavior in adulthood, and its disruption is associated with several psychiatric disorders including schizophrenia (SZ). While acute NMDA receptor (NMDAr) blockade leads to excess glutamate transmission in the PFC, the long-term consequences of MK-801 administration during early adolescence on the E/I balance in adulthood have not been extensively studied. In the current study, we show that chronic MK-801 administration during early adolescence leads to abnormalities in recognition memory and social behavior as well as reduced frequency of miniature inhibitory post-synaptic currents (mIPSCs) in mPFC of adult male rats, with no change in excitatory currents or basal activity. We further show that chemogenetic attenuation of prelimbic mPFC pyramidal neurons reversed deficits in recognition memory, but not social behavior. These findings emphasize the critical role played by NMDAr during adolescence on the E/I balance as well as cognition and social function in adulthood. Moreover, these findings implicate the therapeutic outcomes of reduced mPFC pyramidal neuron activity in recognition memory deficits in early-adolescence MK-801-treated rats. Since recognition memory deficits are key components of the cognitive deficits in SZ, these findings suggest that the future development of treatments aimed at alleviating the cognitive deficits in SZ should focus on regulating the prefrontal E/I balance.

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Section: Discussionmentioning

confidence: 64%

Chemogenetic attenuation of PFC pyramidal neurons restores deficits in recognition memory following adolescent NMDA receptor blockade

Bauminger,

Chandran,

Akirav

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The inhibitory network, comprising distinct classes of interneurons, is a crucial component of hippocampal microcircuits, controlling the spike timing of pyramidal neurons 32 . Among these interneurons, PV interneurons have been identified as essential contributors to information processing and cognitive behavior, maintaining excitation‐inhibition homeostasis of neural circuits 33,34 . Furthermore, accumulating evidence linked the loss and dysfunction of PV interneurons to the pathophysiology of various neuropsychiatric disorders, such as schizophrenia, Alzheimer's disease, and postoperative cognitive impairments 35–37 .…”

Section: Discussionmentioning

confidence: 99%

“… 32 Among these interneurons, PV interneurons have been identified as essential contributors to information processing and cognitive behavior, maintaining excitation‐inhibition homeostasis of neural circuits. 33 , 34 Furthermore, accumulating evidence linked the loss and dysfunction of PV interneurons to the pathophysiology of various neuropsychiatric disorders, such as schizophrenia, Alzheimer's disease, and postoperative cognitive impairments. 35 , 36 , 37 PV interneurons begin to express at P6 and undergo final differentiation at P21, remaining stable at P30.…”

Section: Discussionmentioning

confidence: 99%

SynCAM1 deficiency in the hippocampal parvalbumin interneurons contributes to sevoflurane‐induced cognitive impairment in neonatal rats

Zhao,

Gu,

Pan

et al. 2023

CNS Neurosci Ther

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AimsSevoflurane is widely used for general anesthesia in children. Previous studies reported that multiple neonatal exposures to sevoflurane can induce long‐term cognitive impairment in adolescent rats, but the underlying mechanisms were not defined.MethodsPostnatal day 6 (P6) to P8 rat pups were exposed to 30% oxygen with or without 3% sevoflurane balanced with air. The Y maze test (YMT) and Morris water maze (MWM) tests were performed in some cohorts from age P35 to assess cognitive functions, and their brain samples were harvested at age P14, 21, 28, 35, and 42 for measurements of various molecular entities and in vivo electrophysiology experiments at age P35.ResultsSevoflurane exposure resulted in cognitive impairment that was associated with decreased synCAM1 expression in parvalbumin (PV) interneurons, a reduction of PV phenotype, disturbed gamma oscillations, and dendritic spine loss in the hippocampal CA3 region. Enriched environment (EE) increased synCAM1 expression in the PV interneurons and attenuated sevoflurane‐induced cognitive impairment. The synCAM1 overexpression by the adeno‐associated virus vector in the hippocampal CA3 region restored sevoflurane‐induced cognitive impairment, PV phenotype loss, gamma oscillations decrease, and dendritic spine loss.ConclusionOur data suggested that neonatal sevoflurane exposure results in cognitive impairment through decreased synCAM1 expression in PV interneurons in the hippocampus.

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GABAergic and inflammatory changes in the frontal cortex following neonatal PCP plus isolation rearing, as a dual-hit neurodevelopmental model for schizophrenia

Cale,

Chauhan,

Cleaver

et al. 2024

Mol Neurobiol

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The pathogenesis of schizophrenia begins in early neurodevelopment and leads to excitatory-inhibitory imbalance. It is therefore essential that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar neurochemical deficits. One approach to improved preclinical modelling incorporates dual-hit neurodevelopmental insults, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress). We recently showed that male Lister-hooded rats exposed to PCP-Iso exhibit reduced hippocampal expression of the GABA interneuron marker calbindin. The current study expanded on this by investigating changes to additional populations of GABAergic interneurons in frontal cortical and hippocampal tissue from the same animals (by immunohistochemistry) as well as levels of GABA itself (via ELISA). Because inflammatory changes are also implicated in schizophrenia, we performed additional immunohistochemical evaluations of Iba-1 positive microglia as well as ELISA analysis of IL-6 in the same brain regions. Single-hit isolation-reared and dual-hit PCP-Iso rats both showed reduced parvalbumin immunoreactivity in the prelimbic/infralimbic region of the frontal cortex. However, this was more widespread in PCP-Iso, extending to the medial/ventral and lateral/dorsolateral orbitofrontal cortices. Loss of GABAergic markers was accompanied by increased microglial activation in the medial/ventral orbitofrontal cortices of PCP-Iso, together with frontal cortical IL-6 elevations not seen following single-hit isolation rearing. These findings enhance the face validity of PCP-Iso, and we advocate the use of this preclinical model for future evaluation of novel therapeutics—especially those designed to normalise excitatory-inhibitory imbalance or reduce neuroinflammation.

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Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration

Cited by 11 publications

References 70 publications

Chemogenetic attenuation of PFC pyramidal neurons restores deficits in recognition memory following adolescent NMDA receptor blockade

Chemogenetic attenuation of PFC pyramidal neurons restores deficits in recognition memory following adolescent NMDA receptor blockade

SynCAM1 deficiency in the hippocampal parvalbumin interneurons contributes to sevoflurane‐induced cognitive impairment in neonatal rats

GABAergic and inflammatory changes in the frontal cortex following neonatal PCP plus isolation rearing, as a dual-hit neurodevelopmental model for schizophrenia

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