Interneuron deficits in neurodevelopmental disorders: Implications for disease pathology and interneuron-based therapies

Paternò, Rosalia; Casalia, Mariana L.; Baraban, Scott C.

doi:10.1016/j.ejpn.2019.12.015

Cited by 25 publications

(24 citation statements)

References 100 publications

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“…Many neuropsychiatric disorders – including autism, schizophrenia, depression, and anxiety disorders – are proposed to involve deficits in prefrontal functions and top-down control (Gilbert et al, 2008; Hare and Duman, 2020; Orellana and Slachevsky, 2013), and in particular, altered connectivity and communication between PFC and HPC (Cunniff et al, 2020; Godsil et al, 2013; Kupferschmidt and Gordon, 2018; Li et al, 2015; Sigurdsson et al, 2010). Abnormalities in GABAergic neuron structure and function have also been heavily implicated in the pathophysiology of neuropsychiatric disorders (Chattopadhyaya and Cristo, 2012; Marin, 2012; Paterno et al, 2020). PFC–dHPC LRG projections obviously represent a point of convergence for these different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

Malik

Schamiloglu

et al. 2021

Preprint

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The prefrontal cortex (PFC) is postulated to exert 'top-down control' by modulating information processing throughout the brain to promote specific actions based on current goals. However, the pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down prefrontal control of information processing in the hippocampus remains sparse. Here we describe novel monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal−hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal representations of objects. Correspondingly, stimulation of PFC-to-hippocampus GABAergic projections promotes object exploration. Together, these results elucidate a novel top-down pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

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Section: Discussionmentioning

confidence: 99%

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

Malik

Schamiloglu

et al. 2021

Preprint

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“…Cortical and hippocampal (pallial) inhibitory interneurons are a diverse subset of the total neuronal population, mediate many critical brain functions, and arise from embryonic subpallium regions (Fishell, 2007;Gelman et al, 2012;Kessaris et al, 2014). A wide spectrum of neurological pathologies is associated with loss, or dysfunction, of pallial interneurons including, but not limited to, epilepsy, autism spectrum disorder, Alzheimer's disease and schizophrenia (Marin, 2012;Inan et al, 2013;Paterno et al, 2020). Studies over the past decade demonstrated that transplantation of pallial interneurons offer great promise for treatment of these disorders (Baraban et al, 2009;Alvarez-Buylla et al, 2000;Bráz et al, 2012;Anderson and Baraban, 2012;Hunt et al, 2013;Tong et al, 2014;Donegan et al, 2017;Juarez-Salinas et al, 2019;Zhu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Interneuron origins in the embryonic porcine medial ganglionic eminence

Casalia

Ramsay

et al. 2020

Preprint

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Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6 and Dlx2 expression, in vitro differentiation into neurons expressing GABA and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.Significance StatementHere we demonstrate that porcine MGE, like rodents, exhibit a distinct transcriptional and pallial interneuron-specific antibody profile, in vitro migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic pallial interneuron origins in the pig, and because a rich neurodevelopmental literature on embryonic mouse MGE exists (with some additional characterizations in other species like monkey and human) our work allows direct neurodevelopmental comparisons with this literature.

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“…Lastly, human neonates born before 32 GW exhibit fewer GABAergic interneurons in the white matter and subplate; the density of SST+ and calbindin+ (CB)+ interneurons are significantly decreased in the PFC in these premature cases [ 61 , 62 ]. Thus, defects in inhibitory neurogenesis can decrease the number of cortical interneurons, eventually disrupting the excitatory and inhibitory balance and leading to cognitive deficits, such as those observed in ASD [ 63 , 64 ].…”

Section: Extended Production Of Cortical Gabaergic Interneuronmentioning

confidence: 99%

Implications of Extended Inhibitory Neuron Development

Kim

Paredes

2021

IJMS

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A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.

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Interneuron deficits in neurodevelopmental disorders: Implications for disease pathology and interneuron-based therapies

Cited by 25 publications

References 100 publications

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

Interneuron origins in the embryonic porcine medial ganglionic eminence

Implications of Extended Inhibitory Neuron Development

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