Fetal alcohol exposure can result in life-long cognitive deficiencies. However, the molecular bases of the effects of alcohol on the developing brain have not been clear. Now, Mohammad et al. show in mice that the calcium-activated potassium channel KCNN2 (also known as SK2) is upregulated in cortical neurons following prenatal alcohol exposure and contributes to alcohol-induced deficits in motor skill learning.
The authors studied mice that received an acute prenatal alcohol exposure (PAE) on embryonic day 16 (E16) and E17, when neurons in the upper cerebral cortex are predominantly generated. At postnatal day 30, body weight, brain size and weight, locomotor activity and anxiety-like behaviour did not differ markedly between PAE mice and control mice that had been prenatally exposed to saline. However, motor skill learning was impaired in PAE mice, as reflected by their reduced learning in the accelerated rotarod test compared with controls. Similarly, in a test of fine motor skills, PAE mice were up to 3-fold less successful in reaching for and obtaining a single pellet than were the control mice. Together, these data show that fetal alcohol exposure impairs motor skill learning.
Previous studies in mice revealed that the cytoprotective heat shock signalling pathway is upregulated in neural progenitor cells (NPCs) in the alcohol-exposed fetal brain. Here, the authors used in utero electroporation to selectively express red fluorescent protein (RFP) in NPCs with activated heat shock signalling in the developing primary motor cortex (M1). Alcohol exposure had no obvious effects on NPC proliferation or differentiation, or on the migration or morphology of their excitatory neuron progeny in cortical layers II/III. However, single-cell RNA sequencing revealed altered expression of multiple genes, including some involved in synaptic plasticity and long-term potentiation, in RFP+ neurons compared with RFP− neurons. Notably, the transcriptional profiles of RFP+ neurons were more heterogeneous than those of RFP− neurons, mirroring the heterogeneity in heat shock signalling response in NPCs. Thus, NPC exposure to alcohol has lasting effects on the molecular properties of their neuronal progeny.
RFP+ neurons showed an upregulation of Kcnn2, and KCNN2 expression was higher in the M1 of PAE mice than in that of control mice. Furthermore, electrophysiological abnormalities in layer III RFP+ neurons were reversed by treatment of M1 slices with the KCNN2 blocker tamapin. Importantly, Kcnn2 expression in RFP+ M1 neurons correlated with the learning deficits in PAE mice, and KCNN2 inhibition (by postnatal tamapin administration or Kcnn2 knockdown in layer II and III excitatory neurons in M1) ameliorated the learning deficits in PAE mice.
“KCNN2 inhibition … ameliorated the learning deficits in PAE mice”
This study reveals a role for KCNN2 in motor learning deficits following fetal alcohol exposure and suggests KCNN2 inhibitors may have potential in the treatment of learning disability in individuals with fetal alcohol exposure disorders.
Mohammad, S. et al. Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders. Nat. Neurosci. 23, 533–543 (2020)