Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia

Neurobiol Dis. 2021 Jul;155:105382. doi: 10.1016/j.nbd.2021.105382. Epub 2021 Apr 30.

Abstract

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on the expression of multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in the neocortex of subjects with schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. Therefore, to assess the role of Kv9.3 subunits in PV neuron function, we combined gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice. Kcns3 mRNA levels were ~ 50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing. Moreover, Kcns3 deficiency impaired the recruitment of PVBC firing at gamma frequency by stimuli mimicking synaptic input observed during cortical UP states. Our data indicate that Kv9.3 subunits are critical for PVBC physiology and suggest that KCNS3 deficiency in schizophrenia could impair PV neuron firing, possibly contributing to deficits in cortical gamma oscillations in the illness.

Keywords: Action potential; Basket cells; Gamma oscillations; Kv9.3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Animals
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neurons / physiology*
  • Organ Culture Techniques
  • Parvalbumins / physiology*
  • Potassium Channels, Voltage-Gated / deficiency*
  • Potassium Channels, Voltage-Gated / genetics
  • Prefrontal Cortex / physiopathology*
  • Schizophrenia / genetics
  • Schizophrenia / physiopathology*

Substances

  • KCNS3 protein, human
  • Parvalbumins
  • Potassium Channels, Voltage-Gated