Selective postnatal excitation of neocortical pyramidal neurons results in distinctive behavioral and circuit deficits in adulthood
William E. Medendorp,
Andreas Bjorefeldt,
Emmanuel L. Crespo,
Mansi Prakash,
Akash Pal,
Madison L. Waddell,
Christopher I. Moore,
Ute Hochgeschwender
Affiliations
William E. Medendorp
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA
Andreas Bjorefeldt
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA; Department of Neuroscience, Brown University, Providence, RI 02906, USA
Emmanuel L. Crespo
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA
Mansi Prakash
College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA
Akash Pal
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA
Madison L. Waddell
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA
Christopher I. Moore
Department of Neuroscience, Brown University, Providence, RI 02906, USA; Carney Institute for Brain Science, Brown University, Providence, RI 02906, USA; Corresponding author
Ute Hochgeschwender
Program in Neuroscience, Central Michigan University, Mount Pleasant, MI 48859, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI 48859, USA; Corresponding author
Summary: In genetic and pharmacological models of neurodevelopmental disorders, and human data, neural activity is altered within the developing neocortical network. This commonality begs the question of whether early enhancement in excitation might be a common driver, across etiologies, of characteristic behaviors. We tested this concept by chemogenetically driving cortical pyramidal neurons during postnatal days 4–14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expressing neurons, led to decreased social interaction and increased grooming activity in adult animals. In vivo optogenetic interrogation in adults revealed decreased baseline but increased stimulus-evoked firing rates of pyramidal neurons and impaired recruitment of inhibitory neurons. Slice recordings in adults from prefrontal cortex layer 5 pyramidal neurons revealed decreased intrinsic excitability and increased synaptic E/I ratio. Together these results support the prediction that enhanced pyramidal firing during development, in otherwise normal cortex, can selectively drive altered adult circuit function and maladaptive changes in behavior.
