Biology subjects

Pelkey, K. A.

Publications and source records attributed to Pelkey, K. A..

9 recordsLinked to original sources

bioRxiv2026

Early-life medial pulvinar disruption drives schizophrenia-relevant prefrontal inhibitory and cognitive deficits in primates

Schizophrenia is thought to arise from disrupted postnatal maturation of prefrontal circuits, but the developmental events linking early vulnerability to adult cortical dysfunction remain unclear. Here, we tested whether the primate medial pulvinar, a higher-order thalamic nucleus interconnected with prefrontal cortex, contributes to prefrontal maturation. Bilateral medial pulvinar lesions in neonatal marmosets altered adolescent prefrontal diffusion trajectories and produced adult working memory deficits, the latter of which did not follow comparable lesions in adulthood. Early-life lesioned animals showed reduced thalamocortical input to layer 3 parvalbumin interneurons, diminished prefrontal gamma power, reduced parvalbumin expression, and immature-like physiology in fast-spiking interneurons. These findings reveal a developmental window in which thalamic input shapes prefrontal inhibitory maturation, suggesting that some forms of cortical dysfunction in psychiatric disease originate not in the cortex itself, but in its thalamic inputs.

neuroscience↗

bioRxiv2025

Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution.

Decades of studies implicating GluN3A N-methyl-D-aspartate receptor (NMDAR) subunits in physiological and pathological function have largely been interpreted through direct regulation of conventional glutamatergic NMDARs. However, emerging evidence indicates that GluN3A frequently assembles with GluN1 forming unconventional glutamate-insensitive NMDARs that operate as native excitatory glycine receptors (eGlyRs). Here we demonstrate that hippocampal somatostatin and neurogliaform interneurons (Sst-INs and NGFCs) express functional eGlyRs from early postnatal through adult ages. In the developing hippocampus eGlyR-mediated excitation of NGFCs with ambient glycine dramatically increases GABAergic tone, with consequences for the generation of giant depolarizing potentials (GDPs). In the mature hippocampus, eGlyR- mediated excitation of Sst-INs regulates sharp wave ripples (SWRs). Finally, we reveal evolutionary conservation of hippocampal Sst-IN eGlyRs and eGlyR- mediated SWR regulation in non-human primates confirming functional eGlyR availability for therapeutic potential in higher species. Our findings underscore that eGlyR mediated regulation of cell and circuit excitability through both cell autonomous and cell non-autonomous mechanisms must be considered to understand GluN3A roles in brain development, plasticity, and disease.

neuroscience↗

bioRxiv2025

A novel, evolutionarily conserved inhibitory circuit selectively regulates dentate gyrus mossy cell function.

The mammalian dentate gyrus contributes to mnemonic function by parsing similar events and places. The disparate activity patterns of mossy cells and granule cells is believed to enable this function yet the mechanisms that drive this circuit dynamic remain elusive. We identified a novel inhibitory interneuron subtype, characterized by VGluT3 expression, with overwhelming target selectivity for mossy cells while also revealing that CCK, PV, SOM and VIP interneurons preferentially innervate granule cells. Leveraging pharmacology and novel enhancer viruses, we find that this target-specific inhibitory innervation pattern is evolutionarily conserved in non-human primates and humans. In addition, in vivo chemogenetic manipulation of VGluT3+ interneurons selectively alters the activity and functional properties of mossy cells. These findings establish that mossy cells and granule cells have unique, evolutionarily conserved inhibitory innervation patterns and suggest selective inhibitory circuits may be necessary to maintain DG circuit dynamics and enable pattern separation across species.

neuroscience↗

bioRxiv2024

Complex opioid driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward and addiction.

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical and cellular components which, in concert, perform computations to drive emotion, reward and addiction behaviors. Although housing one of the most prominent mu opioid receptor (mOR) expression levels in the brain, remarkably little is known as to how they impact mHb/IPN circuit function at the granular level. In this study, our systematic functional and pharmacogenetic analyses demonstrate that mOR activation attenuates glutamatergic signaling whilst producing an opposing potentiation of glutamatergic/cholinergic co-transmission mediated by mHb substance P and cholinergic neurons, respectively. Intriguingly, this latter non-canonical augmentation is developmentally regulated only emerging during later postnatal stages. In addition, we reveal that specific potassium channels act as a molecular brake on nicotinic receptor signaling in the IPN with the opioid mediated potentiation of this arm of neurotransmission being operational only following attenuation of Kv1 function. Thus, mORs play a complex role in shaping the salience of distinct afferent inputs and transmitter modalities that ultimately influences synaptic recruitment of downstream GABAergic IPN neurons. Together, these observations provide a framework for future investigations aimed at identifying the neural underpinnings of maladaptive behaviors that can emerge when opioids, including potent synthetic analogs such as fentanyl, modulate or hijack this circuitry during the vulnerable stages of adolescence and in adulthood.

neuroscience↗

bioRxiv2024

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development

Within the adult rodent hippocampus, opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting local micro-circuits. However, it is unknown if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in hippocampus proper but not primary neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate early population activity. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

neuroscience↗

bioRxiv2021

The GluN2A subunit of the NMDA receptor modulates the rate of functional maturation in parvalbumin-positive interneurons

N-methyl-D-aspartate receptors (NMDARs) comprise a family of ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (encoded by the GRIN1 gene) and two GluN2 subunits (encoded by the GRIN2A-GRIN2D genes). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. To explore this new clinical finding at that circuit and cellular level, we conducted studies using Grin2a+/- and Grin2a-/-mice at various stages during neurodevelopment. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a+/- and Grin2a-/- mice. These alterations in somatic spiking are not due to global upregulation other GRIN genes (including Grin2b) nor can they be attributed to perturbations in the intrinsic excitability or action-potential firing properties of CA1 pyramidal cells. Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of PV interneurons. Overall, we report that Grin2a+/+ mice reach electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a+/- mice not reaching electrophysiological maturation until preadolescence, and Grin2a-/- not reaching electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure burden in disease-associated null GRIN2A patients.

neuroscience↗

bioRxiv2020

NMDAR-mediated transcriptional control of geneexpression in the specification of interneuron subtype identity

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+ and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical and physiological properties. However, the molecular mechanisms regulating their diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

neuroscience↗

bioRxiv2020

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance to human circuit function. In this study, we focus on neurogliaform cells, a specialized form of neuron that possess physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms relevant for human cognitive processing and behavior.

neuroscience↗

bioRxiv2019

Viral manipulation of functionally distinct neurons from mice to humans

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

neuroscience↗