Developmental regulation of excitatory-inhibitory synaptic balance in the prefrontal cortex during adolescence

doi:10.1016/j.semcdb.2021.02.008

Seminars in Cell & Developmental Biology

Volume 118, October 2021, Pages 60-63

https://doi.org/10.1016/j.semcdb.2021.02.008 Get rights and content

Highlights

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The prefrontal excitatory-inhibitory (E-I) balance is actively changing during adolescence.
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A gain of GABA function during late adolescence dictates the prefrontal E-I balance.
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Reduced GABA function up to adolescence can permanently alter prefrontal E-I ratio.

Abstract

The prefrontal cortex (PFC) is a cortical structure involved in a variety of complex functions in the cognitive and affective domains. The intrinsic function of the PFC is defined by the interaction of local glutamatergic and GABAergic neurons and their modulation by long-range inputs. The ensuing interactions generate a ratio of excitation and inhibition (E-I) in each output neuron, a balance which is refined during the adolescent to adult transition. In this short review, we aim to describe how an increase in GABAergic transmission during adolescence modifies the E-I ratio in adults. We further discuss how this new setpoint may change the dynamics of PFC networks observed during the transition to adulthood.

Introduction

The prefrontal cortex (PFC) undergoes a period of protracted development that spans adolescence until early adulthood [1], [2]. It is thought such a delayed maturation is responsible for the acquisition of adult cognitive abilities later in life particularly in the domains of decision-making, attention, learning, memory, and affect regulation. Due to this developmental feature, the time window during which the PFC is susceptible to environmental interference is longer than for other cortical regions. When compounded with the increase in experimentation and risk-taking also observed during adolescence [3], PFC disruption can have negative consequences in the acquisition of adult behavior. Here we discuss how PFC maturation during adolescence can be understood as a function of the excitation-inhibition (E-I) balance.

Section snippets

The E-I ratio and PFC development

The biological underpinnings behind prefrontal maturation are only beginning to be understood. At the cellular level, PFC activity is defined by the interaction of local GABAergic interneurons and pyramidal cells as well as glutamatergic projections from other limbic structures, and most notably, frontal-projecting dopamine cells in the ventral tegmental area (VTA). Thus, the resulting PFC output function is broadly the sum of inhibitory (GABAergic) and excitatory (glutamatergic) transmission

Studies in animal models

Over the years, our laboratory and others have documented a developmental recruitment of inhibitory transmission in the PFC up to late adolescence (postnatal day -P- 50 in rats) without a concurrent increase in basal excitatory transmission [10], [11], [12], [13]. In other words, the E-I ratio of layer V pyramidal neurons is actively readjusting during adolescence due to the gain of local GABAergic transmission (Fig. 1). This fits with the model of protracted development of the GABAergic

The E-I balance in humans

The overproduction and subsequent loss of spines observed in rodents and non-human primates during adolescence is also recapitulated in the human PFC extending until early adulthood [27]. This late pruning of synapses and dendrites is likely to underlie the decrease in cortical thickness that occurs in frontal areas during development [2]. This is accompanied by a “stabilization” of remaining connections, which may mediate the changes in global E-I ratio observed during adolescence.

Outstanding questions

Several observations in pre-clinical and clinical models point towards the E-I balance being disrupted in developmental disorders such as schizophrenia and autism. It is possible that multiple neurotransmitter systems contribute to fine-tuning the E-I balance in the PFC during adolescence. The synaptic contribution of each afferent/input to PFC output computation remains to be studied.

Similarly, while it is known that disruption of prefrontal E-I balance affects PFC-dependent behaviors, the

Conclusions

The E-I ratio of PFC output neurons is refined during adolescence by an increase in GABAergic function. As such, adolescence constitutes a period of exquisite sensitivity to environmental disruption that can have long-lasting consequences in PFC output function. This susceptibility stems from an apparent arrest in the development of local prefrontal GABAergic network that reaches its maturation late in adolescence. Multiple layers of neuromodulators aid in the maturation of PFC GABAergic

Acknowledgements

This work was supported by the National Institute of Mental Health (USA) grants MH086507, MH105488, and MH123147 to KYT. Funding source had no role in the study design, data analysis, or writing of this report. Authors have no additional disclosures.

Conflict of interest

None.

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Adolescence has been hypothesized to be a critical period for the development of human association cortex and higher-order cognition. A defining feature of critical period development is a shift in the excitation: inhibition (E/I) balance of neural circuitry, however how changes in E/I may enhance cortical circuit function to support maturational improvements in cognitive capacities is not known. Harnessing ultra-high field 7 T MR spectroscopy and EEG in a large, longitudinal cohort of youth (N = 164, ages 10–32 years old, 347 neuroimaging sessions), we delineate biologically specific associations between age-related changes in excitatory glutamate and inhibitory GABA neurotransmitters and EEG-derived measures of aperiodic neural activity reflective of E/I balance in prefrontal association cortex. Specifically, we find that developmental increases in E/I balance reflected in glutamate:GABA balance are linked to changes in E/I balance assessed by the suppression of prefrontal aperiodic activity, which in turn facilitates robust improvements in working memory. These findings indicate a role for E/I-engendered changes in prefrontal signaling mechanisms in the maturation of cognitive maintenance. More broadly, this multi-modal imaging study provides evidence that human association cortex undergoes physiological changes consistent with critical period plasticity during adolescence.
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Binge drinking during adolescence is highly prevalent despite increasing evidence of its long-term impact on behaviors associated with modulation of behavioral flexibility by the medial prefrontal cortex (mPFC). In the present study, male and female rats underwent adolescent intermittent ethanol (AIE) exposure by vapor inhalation. After aging to adulthood, retrograde bead labelling and viral tagging were used to identify populations of neurons in the prelimbic region (PrL) of the mPFC that project to specific subcortical targets. Electrophysiological recording from bead-labelled neurons in PrL slices revealed that AIE did not alter the intrinsic excitability of PrL neurons that projected to either the NAc or the BLA. Similarly, recordings of spontaneous inhibitory and excitatory post-synaptic currents revealed no AIE-induced changes in synaptic drive onto either population of projection neurons. In contrast, AIE exposure was associated with a loss of dopamine receptor 1 (D1), but no change in dopamine receptor 2 (D2), modulation of evoked firing of both populations of projection neurons. Lastly, confocal imaging of proximal and apical dendritic tufts of viral-labelled PrL neurons that projected to the nucleus accumbens (NAc) revealed AIE did not alter the density of dendritic spines. Together, these observations provide evidence that AIE exposure results in disruption of D1 receptor modulation of PrL inputs to at least two major subcortical target regions that have been implicated in AIE-induced long-term changes in behavioral control.
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Citation Excerpt :
Underlying this transitional developmental period might be heightened neural plasticity consistent with a critical period. At the molecular level, animal and postmortem human studies show changes in GABA and glutamate in PFC (Caballero et al., 2021), which has been proposed to be consistent with a model of adolescence as a developmental critical period for executive function (Larsen and Luna, 2018). Studies in animal model sensory systems have demonstrated that a key mechanism regulating the opening of a critical period is a shift in the excitation/inhibition (E/I) balance.
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View full text

Developmental regulation of excitatory-inhibitory synaptic balance in the prefrontal cortex during adolescence

Highlights

Abstract

Introduction

Section snippets

The E-I ratio and PFC development

Studies in animal models

The E-I balance in humans

Outstanding questions

Conclusions

Acknowledgements

Conflict of interest

Neurosci. Biobehav. Rev.

Biol. Psychiatry

Neurosci. Biobehav Rev.

Biol. Psychiatry

Neuron

Brain Res.

Neurosci. Biobehav Rev.

Neuroimage

Mapping cortical change across the human life span

Nat. Neurosci.

Dynamic mapping of human cortical development during childhood through early adulthood

Proc. Natl. Acad. Sci. U. S. A.

Dopamine modulation of GABAergic function enables network stability and input selectivity for sustaining working memory in a computational model of the prefrontal cortex

Neuropsychopharmacology

Functional maps of neocortical local circuitry

Front Neurosci.

N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning

Behav. Neurosci.

Prefrontal dopamine and behavioral flexibility: shifting from an “inverted-U” toward a family of functions

Front Neurosci.

Neocortical excitation/inhibition balance in information processing and social dysfunction

Nature

CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex

Mol. Psychiatry

Functional maturation of GABA synapses during postnatal development of the monkey dorsolateral prefrontal cortex

Cereb. Cortex