Calcium-permeable AMPA receptors govern PV neuron feature selectivity

Ingie Hong; Juhyun Kim; Thomas Hainmueller; Dong Won Kim; Joram Keijser; Richard C Johnson; Soo Hyun Park; Nathachit Limjunyawong; Zhuonan Yang; David Cheon; Taeyoung Hwang; Amit Agarwal; Thibault Cholvin; Fenna M Krienen; Steven A McCarroll; Xinzhong Dong; David A Leopold; Seth Blackshaw; Henning Sprekeler; Dwight E Bergles; Marlene Bartos; Solange P Brown; Richard L Huganir

doi:10.1038/s41586-024-08027-2

Calcium-permeable AMPA receptors govern PV neuron feature selectivity

Nature. 2024 Nov;635(8038):398-405. doi: 10.1038/s41586-024-08027-2. Epub 2024 Oct 2.

Authors

Ingie Hong^#^{1

2}, Juhyun Kim^#^{3

4

5}, Thomas Hainmueller^#^{6

7}, Dong Won Kim^{3

8

9}, Joram Keijser^{10

11}, Richard C Johnson^{3

12}, Soo Hyun Park^{13

14}, Nathachit Limjunyawong^{3

15}, Zhuonan Yang^{3

12}, David Cheon^{3

12}, Taeyoung Hwang^{3

16

17}, Amit Agarwal^{3

18

19}, Thibault Cholvin⁶, Fenna M Krienen²⁰, Steven A McCarroll²¹, Xinzhong Dong^{3

22}, David A Leopold¹³, Seth Blackshaw^{3

12

23

24}, Henning Sprekeler^{10

25

26}, Dwight E Bergles^{3

12}, Marlene Bartos⁶, Solange P Brown^{3

12}, Richard L Huganir^{27

28}

Affiliations

¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ingiehong@jhmi.edu.
² Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA. ingiehong@jhmi.edu.
³ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.
⁶ Institute for Physiology I, University of Freiburg, Medical Faculty, Freiburg, Germany.
⁷ Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA.
⁸ Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark.
⁹ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
¹⁰ Modelling of Cognitive Processes, Technical University of Berlin, Berlin, Germany.
¹¹ Charité-Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin, Berlin, Germany.
¹² Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA.
¹³ Section on Cognitive Neurophysiology and Imaging, National Institute of Mental Health, Bethesda, MD, USA.
¹⁴ Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
¹⁵ Center of Research Excellence in Allergy and Immunology, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
¹⁶ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
¹⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg, Germany.
¹⁹ Interdisciplinary Center for Neurosciences, University of Heidelberg, Heidelberg, Germany.
²⁰ Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA.
²¹ Department of Genetics, Harvard Medical School, Boston, MA, USA.
²² Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²³ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁴ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany.
²⁶ Science of Intelligence, Research Cluster of Excellence, Berlin, Germany.
²⁷ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rhuganir@jhmi.edu.
²⁸ Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA. rhuganir@jhmi.edu.

^# Contributed equally.

Abstract

The brain helps us survive by forming internal representations of the external world^1,2. Excitatory cortical neurons are often precisely tuned to specific external stimuli^3,4. However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective⁵. PV interneurons differ from excitatory neurons in their neurotransmitter receptor subtypes, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs)^6,7. Excitatory neurons express calcium-impermeable AMPARs that contain the GluA2 subunit (encoded by GRIA2), whereas PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find low expression stoichiometry of GRIA2 mRNA relative to other subunits in PV interneurons that is conserved across ferrets, rodents, marmosets and humans, and causes abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Manipulations to induce sparse CP-AMPAR expression demonstrated that this increase was cell-autonomous and could occur with changes beyond development. Notably, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, which suggested that the selectivity of PV interneurons can be altered without markedly changing connectivity. In Gria2-knockout mice, in which all AMPARs are calcium-permeable, excitatory neurons showed significantly degraded orientation selectivity, which suggested that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Moreover, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, which indicated that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a new role of CP-AMPARs in maintaining low-selectivity sensory representation in PV interneurons and implicate a conserved molecular mechanism that distinguishes this cell type in the neocortex.

MeSH terms

Animals
Calcium* / metabolism
Callithrix / metabolism
Female
Hippocampus / cytology
Hippocampus / metabolism
Humans
Interneurons* / metabolism
Male
Mice
Parvalbumins* / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, AMPA* / deficiency
Receptors, AMPA* / genetics
Receptors, AMPA* / metabolism
Visual Cortex* / cytology
Visual Cortex* / metabolism
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism

Substances

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Calcium
glutamate receptor ionotropic, AMPA 2
Parvalbumins
Receptors, AMPA
RNA, Messenger