Excitability governs neural development in a hippocampal region specific manner

Abstract

Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability.

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Here we show that PPA affects the much smaller part of the hippocampus, while the prefrontal cortex retained almost normal ultrastructure. It is also notable that during adolescence, molecular composition and synaptic function of both regions still undergo developmental modifications, indicating to a high level of neuroplasticity of these areas in response to physiological and pathological conditions (Counotte et al, 2010;Gómez & Edgin, 2016;Johnson-Venkatesh, Khan, Murphy, Sutton, & Umemori, 2015).…”

Prolonged maternal separation attenuates BDNF‐ERK signaling correlated with spine formation in the hippocampus during early brain development

“…; Johnson‐Venkatesh et al . ). Given that these events are organized in a highly orderly manner, MS could interrupt normal neural network formation even if it is transient during early brain development.…”

Retrograde fibroblast growth factor 22 (FGF22) signaling regulates insulin-like growth factor 2 (IGF2) expression for activity-dependent synapse stabilization in the mammalian brain

“…These results indicate that neural activity is not required for FGF22 to induce IGF2 expression, but is necessary for IGF2 to localize to and organize development of presynaptic terminals. To confirm that the activity of presynaptic neurons is critical for the localization and function of IGF2, we suppressed intrinsic neuronal excitability of DGCs by sparsely transfecting the inwardly rectifying potassium channel, Kir2.1, in culture ( Johnson-Venkatesh et al, 2015 ). Similarly to the results with TTX, Kir2.1 expression in DGCs decreased the synaptic localization of IGF2 ( Figure 6G and H ) and completely blocked the synaptogenic function of IGF2 ( Figure 6I and J ).…”

“…Various forms of activity are involved: in most cases, synaptic transmission and synaptic competition are considered critical for synapse refinement ( Lichtman and Colman, 2000 ; Waites et al, 2005 ). In addition, intrinsic activity also plays critical roles in synapse development ( Johnson-Venkatesh et al, 2015 ). However, the molecular mechanisms by which intrinsic activity contributes to synapse stabilization during development are largely unknown.…”