Dendritic Morphology and Inhibitory Regulation Distinguish Dentate Semilunar Granule Cells from Granule Cells through Distinct Stages of Postnatal Development

Abstract

2Semilunar granule cells (SGCs) have been proposed as a morpho-functionally distinct class of 3 hippocampal dentate projection neurons contributing to feedback inhibition and memory 4 processing in juvenile rats. However, whether SGCs retain their unique structural and inhibitory 5 characteristics through postnatal development remains unresolved. Focusing on postnatal days 6 11-13, 28-42, and >120, corresponding with human infancy, adolescence, and adulthood, we 7 examined whether SGCs differ from granule cells (GCs) in somatodendritic morphology and 8 inhibitory regulation. Unsupervised cluster analysis confirmed that morphological features 9 distinguish SGCs from GCs irrespective of animal age. SGCs maintain higher spontaneous 10 inhibitory postsynaptic current (sIPSC) frequency than GCs from infancy through adulthood. 11While sIPSC frequency peaked during adolescence, and amplitude declined progressively with 12 age in both cell types, sIPSC frequency in SGCs was particularly enhanced during adolescence. 13Like GABAergic synaptic inputs, extrasynaptic GABA current amplitude in SGCs peaked in 14 adolescence and was greater than in GCs. Consistent with the developmental profile of SGC 15 synaptic and extrasynaptic GABA currents, perforant-path evoked dentate population responses 16 in vivo showed greater paired-pulse depression during adolescence. These findings highlight the 17 distinct morphology and inhibitory regulation of SGCs through development and suggest that the 18 particularly heightened inhibition of SGCs may shape dentate output during adolescence. 19

Long-term effects of moderate concussive brain injury during adolescence on synaptic and tonic GABA currents in dentate projection neurons

“…Since injury-induced changes in tonic GABA currents differ between GC and SGCs (Gupta et al, 2012), presence of 1-2 primary dendrites and compact dendritic arbors of biocytin filled cells was used to identify GCs (Fig. 1 A-B, Gupta et al, 2020). Tonic GABA current amplitude in GCs remained larger than in agematched sham controls one-month post-FPI (Fig 1C-D and Table 1 & 2) as reported at one week (Fig.…”

“…Kynurenic acid (3 mM KynA), a glutamate receptor antagonist, was used to isolate GABA currents in cells held at -70 mV. SGCs were distinguished by large dendritic angle, multiple primary dendrites, presence of dendritic spines, and axon projecting to the hilus (Gupta et al, 2020). Recordings were discontinued if series resistance increased by >20%.…”

“…This clinically-relevant adolescent concussive injury paradigm impairs working memory performance one to four weeks post-injury followed by an apparent recovery yet heightened risk for seizures one to three months after injury (Neuberger et al, 2017b;Korgaonkar et al, 2020b;Korgaonkar et al, 2020a). Since GABAergic signaling which critically regulates dentate memory function and epileptogenesis (Dengler and Coulter, 2016) undergoes developmental plasticity spanning this period (Kapur and Macdonald, 1999;Gupta et al, 2020), it is important to determine if GC inhibition undergoes progressive changes after concussive TBI.…”

“…In addition to GCs, we reported that brain injury impacts inhibition in semilunar granule cells (SGCs), a sparse morphologically distinct dentate projection neuron (Williams et al, 2007;Gupta et al, 2012;Gupta et al, 2020). Interestingly, both tonic and synaptic GABA currents in SGCs are decreased one week after FPI, which contrasts with increases observed in GCs at the same time (Gupta et al, 2012).…”

“…Since changes in tonic GABA currents enhance SGC excitability early after brain injury (Gupta et al, 2012), changes in SGC inhibition could contribute to posttraumatic memory dysfunction. While SGC tonic GABA currents are greater than in GCs during adolescence, they undergo a developmental decline into adulthood (Gupta et al, 2012;Gupta et al, 2020). Thus, whether the early decrease in SGC tonic GABA currents after injury persists at later time points when SGC tonic GABA currents have declined remains to established.…”