Adolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent

Abstract

The maturation of inhibitory circuits during adolescence may be tied to the onset of mental health disorders such as schizophrenia. Neurotrophin signaling likely plays a critical role in supporting inhibitory circuit development and is also implicated in psychiatric disease. Within the neocortex, subcircuits may mature at different times and show differential sensitivity to neurotrophin signaling. We measured miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs) in Layer 5 cell-types in the mouse anterior cingulate (Cg) across the periadolescent period. We differentiated cell-types mainly by Thy1 YFP transgene expression and also retrobead injection labeling in the contralateral Cg and ipsilateral pons. We found that YFP− neurons and commissural projecting neurons had lower frequency of mIPSCs than neighboring YFP+ neurons or pons projecting neurons in juvenile mice (P21–25). YFP− neurons and to a lesser extent commissural projecting neurons also showed a significant increase in mIPSC amplitude during the periadolescent period (P21–25 vs. P40–50), which was not seen in YFP+ neurons or pons projecting neurons. Systemic disruption of tyrosine kinase receptor B (TrkB) signaling during P23–50 in TrkBF616A mice blocked developmental changes in mIPSC amplitude, without affecting miniature excitatory post synaptic currents (mEPSCs). Our data suggest that the maturation of inhibitory inputs onto Layer 5 pyramidal neurons is cell-type specific. These data may inform our understanding of adolescent brain development across species and aid in identifying candidate subcircuits that may show greater vulnerability in mental illness.

Ovarian Hormones Organize the Maturation of Inhibitory Neurotransmission in the Frontal Cortex at Puberty Onset in Female Mice

“…Our current study included only females, however, we previously found that inhibitory neurotransmission matures similarly between P25 and P40 in layer 5 in males and females [33]. Androgen and estrogen receptor expression is also comparable between sexes in rats [17], and aromatase can convert androgens to estrogens, enabling signaling via estrogen receptors in either sex.…”

“…This shift in E/I balance is likely a key mechanism regulating sensitive period plasticity in primary sensory cortices [30–32]. We have previously demonstrated a striking rise in the strength of inhibitory neurotransmission in deep layers of the frontal cortex during early adolescence[33], which led us to develop a working model in which gonadal steroids drive frontal cortex maturation by increasing the strength of local inhibitory neurotransmission[1]. …”

Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor

“…Adult male and female mice (>P60) were used for all surgeries. Bilateral viral injections were performed using previously described procedures 47 at the following stereotaxic coordinates: dorsomedial prefrontal cortex (dmPFC): 1.94 mm from Bregma, 0.34 mm lateral from midline, and 0.70 mm vertical from cortical surface; substantia nigra pars compacta (SNc): -3.08 mm from Bregma, 1.25 mm lateral from midline, and 4.0 mm vertical from cortical surface. For glutamatergic corticostriatal axon stimulation experiments, mice were injected with 0.5 µL of CAG-ChR2-EYFP virus bilaterally into dmPFC.…”

Periadolescent Maturation of GABAergic Hyperpolarization at the Axon Initial Segment

“…Prefrontal cortex (PFC) circuits, which are involved in high-order decision making and risk assessment, undergo a high degree of refinement and maturation during adolescence (Johnson et al, 2016; Lewis, 1997). GABAergic inhibitory circuits, including parvalbumin-positive chandelier cells, are a major site of adolescent maturation in the PFC (Taniguchi et al, 2013; Uhlhaas and Singer, 2011; Vandenberg et al, 2015). Chandelier cells are thought to regulate large PFC networks, as their dendrites sample associative inputs from other cortical regions, and their axons diverge to synapse onto hundreds of glutamatergic pyramidal cells (Inan et al, 2013).…”