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Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 2021 Sep 8;288(1958):20211025. doi: 10.1098/rspb.2021.1025

The critical period: neurochemical and synaptic mechanisms shared by the visual cortex and the brain stem respiratory system

Margaret T T Wong-Riley 1,✉
PMCID: PMC8424345  PMID: 34493083

Abstract

The landmark studies of Wiesel and Hubel in the 1960's initiated a surge of investigations into the critical period of visual cortical development, when abnormal visual experience can alter cortical structures and functions. Most studies focused on the visual cortex, with relatively little attention to subcortical structures. The goal of the present review is to elucidate neurochemical and synaptic mechanisms common to the critical periods of the visual cortex and the brain stem respiratory system in the normal rat. In both regions, the critical period is a time of (i) heightened inhibition; (ii) reduced expression of brain-derived neurotrophic factor (BDNF); and (iii) synaptic imbalance, with heightened inhibition and suppressed excitation. The last two mechanisms are contrary to the conventional premise. Synaptic imbalance renders developing neurons more vulnerable to external stressors. However, the critical period is necessary to enable each system to strengthen its circuitry, adapt to its environment, and transition from immaturity to maturity, when a state of relative synaptic balance is attained. Failure to achieve such a balance leads to neurological disorders.

Keywords: BDNF, critical period, GABAergic inhibition, postnatal development, synaptic imbalance

1. Introduction

The pioneering work of Wiesel & Hubel [1] on the detrimental effects of monocular deprivation during a critical period of postnatal development spawned a new field of research. Many morphological, neurochemical and physiological underpinnings of cortical plasticity have been identified and expertly reviewed [2–6]. Much less is known of a critical period in the brain stem respiratory system. Rather than focusing on the exhaustively examined topic of plasticity, the present review aims to decipher neurochemical and synaptic mechanisms shared by the primary visual cortex and the subcortical respiratory system in the normal rat.

The brain stem respiratory system is located in both the medulla and the pons, but the focus of this review is on the medullary group, whose development was monitored on a daily basis. Maturational changes in the pontine nuclei involved in the Hering-Breuer reflex will not be detailed here.

2. What is a critical period?

The term ‘critical period’ was originally applied to the imprinting period of greylag birds [7]. Later, it was used for the acquisition time of songs in birds and language in humans [8]. It also refers to a time when auditory and visual maps align in the barn owl tectum for accurate sound localization with respect to visual space [9].

The first indication that the critical period may be harmful to the animal was the groundbreaking work of Wiesel and Hubel. They discovered that monocular deprivation of kittens and young monkeys during, and only during, a critical period leads to abnormal physiological and structural changes in the deprived visual cortex [1,10]. Subsequently, many visual, somatosensory, auditory and other plastic changes during sensitive periods of cortical development were recognized. For example: whisker trimming in rodents disrupts neuronal receptive field structures in deprived barrel cortex [11]; exposing rat pups to pulsed white noise degrades frequency selectivity and tonotopicity in the deprived auditory cortex [12]; and transient olfactory deprivation causes structural changes in the olfactory bulb and prevents the addition of interneuronal subtypes even after naris reopening [13].

In the brain stem respiratory system, a critical period was proposed as one of the three risk factors for sudden infant death syndrome (SIDS) [14]. When and only when all three risk factors occur simultaneously (a vulnerable infant, exposed to an external stressor, during a critical period of postnatal development) does a seemingly normal infant succumb to SIDS.

Thus, the emphasis of the critical period has shifted to a susceptible time when sensory perturbations can be detrimental to the system and the organism. It acquired a negative connotation.

3. Timing of the critical period

The timing of the critical period varies among species, modalities, systems, regions and subregions [15]. The duration can be hours, such as visual imprinting [7], or days, as in the rat respiratory system [16]. Usually, it lasts a week or longer in the rodent cortex, or months to years in the human cortex [17,18]. However, the reported timing often differs widely among studies of the same system [19,20]. This is because developmental changes are often spot-checked across ages, ambiguating the exact timing. Furthermore, plasticity is often equated with the presence of a critical period, including milder forms before and after the period, and even into adulthood [4,5]. The critical period, in the strictest sense, is when plasticity is the most robust.

Most studies referred to two papers [18,21] in ascribing the critical period of the rodent visual cortex as between the third to the fifth postnatal week. However, both papers reported that ‘the maximal effects of monocular deprivation are between the fourth and fifth week’, ‘starting at P28’. Significantly, this is also a time of significant neurochemical and synaptic changes [22] (detailed below) and can thus be regarded as the peak, if not the major component, of the critical period.

Earlier studies on the rat's respiratory system placed the critical period at the end of the first postnatal week [23]. However, later detailed investigations point towards the end of the second week (P12–13) as the most vulnerable period [16,24].

Unlike visual imprinting in birds that onsets right after hatching, most critical periods commence weeks after sensory exposure. Typically, postnatal development begins with an experience-independent phase, when neural connections and basic properties are established innately, guided by molecular signalling and spontaneous neural activity. It then transitions into an experience-dependent plastic stage, the critical period, when neuronal structure and function can be moulded by environmental cues [25], and adaptation to afferent inputs by fine-tuning and shaping of synaptic contacts is an important part of the maturational process [26,27].

Although the timing of the critical period is innately determined, it can be altered experimentally through pharmacological, genetic or other means [28,29]. Thus, critical period timing itself is plastic.

4. What are the neurochemical and synaptic mechanisms underlying the critical period shared by the visual cortex and the brain stem respiratory system?

Multiple intracellular and extracellular agents are involved in cortical plasticity during the critical period, such as the activation of tissue plasminogen activators, endocannabinoids, orthodenticle homeobox 2 (Otx2), neuregulin, extracellular signal-regulated kinase 1,2 (ERK1/2) and epigenetic factors, whereas plasticity is inhibited by such agents as perineuronal nets, myelin and Nogo receptors [4,5,30]. These agents have been well characterized in the murine visual cortex, but little studied in the rat visual cortex or the respiratory system.

When comparing the visual cortex and brain stem respiratory nuclei of normal rats, three basic neurochemical and synaptic mechanisms emerge as common to both of their critical periods.

(a) . Period of heightened inhibition

By far, the leading contributor to critical period opening in the visual cortex is the rise in GABAergic inhibition. This was first noted by Hensch et al. [31], who found that knocking out an important synthetic enzyme of GABA (GAD65) disrupts experience-dependent ocular dominance plasticity in mice, unless a modulator of the GABAA receptor (benzodiazepine) is administered. When given before the critical period, benzodiazepine induces a precocious sensitivity to visual deprivation [32]. Among the different types of GABAergic interneurons, the major players are the large, fast-spiking, calcium-binding, basket parvalbumin (PV)-positive interneurons that make potent axo-somatic synapses onto pyramidal neurons [33,34]. The key GABAA receptor subunit is α1, as its knockin mutation renders the receptors insensitive to benzodiazepine and the critical period cannot be accelerated [35].

The exact timing of the inhibitory rise in the rodent visual cortex was unclear. Recently, Zhang et al. [22] undertook a day-to-day monitoring (from P14 to P36) of spontaneous inhibitory postsynaptic currents (sIPSCs) in layer V pyramidal neurons of the rat visual cortex. They found that, against a gradual rise in both the amplitude and frequency of sIPSCs with age, there was a sudden upsurge in both from P28 to P33/34, before returning to P27 levels at P34/35 (figure 1a,b). This highlights the end of fourth to the end of fifth postnatal weeks as a prominent inhibitory period.

Figure 1.

Figure 1.

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Mean amplitudes and frequencies of sIPSCs (a,b) and sEPSCs (c,d) were recorded daily (P14–P36) from layer V pyramidal neurons of the rat visual cortex. Circled regions denote the critical period when amplitudes and frequencies of sIPSCs rise sharply while those of sEPSCs fall steeply from P28 until P34, when all returned to P27 levels (modified from [22]). Mean sIPSCs (e,f) and sEPSCs (g,h) in respiratory neurons during postnatal development. Circled time points (P12–13) represent the critical period when sIPSCs rise significantly while sEPSCs fall drastically (modified from [36]). ***p < 0.001; **p < 0.01; *p < 0.05 (Tukey's test comparing adjacent age groups). (Online version in colour.)

Likewise, in the brain stem of rats, both the amplitude and frequency of sIPSCs increase significantly in respiratory-related nuclei during a brief, 2-day critical period at P12–P13 (figure 1e,f) [36], when the animals' response to acute hypoxia is the weakest [37].

Neurochemically, the level of GABAARα1 immunoreactivity in single neurons of layers II-VI of the rat visual cortex rises gradually from P14 to P36 [22]. This agrees with a threefold increase in the total GABAergic input converging onto layer II/III pyramidal neurons [38]. In the respiratory system, GABA predominates in the early part of postnatal development, but glycine takes over as the dominant one during the second week [36]. Nevertheless, both GABA and glycine receptor immunoreactivity exhibit a sharp rise in multiple respiratory nuclei at P12 not seen in the non-respiratory nucleus [39,40].

A developmental switch in dominance from the neonatal α3 to the mature α1 subunit of the GABAA receptor occurs during the critical period in the cat visual cortex [41]. A similar switch is reported in the rat visual cortex, but the precise timing was not specified, as the authors assumed no further change beyond P21 [42]. The thalamic GABAARα1-mediated inhibitory circuit also contributes to the regulation of cortical plasticity [43]. In the respiratory system, a switch in dominance from the α3 to the α1 subunit of GABAA receptor occurs at or close to P12 [44,45], the critical period, as does a switch from the neonatal GlyRα2/α3 to the adult GlyRα1 subunit of the glycine receptor and an enhanced expression of GlyRα1 in multiple respiratory nuclei [46].

Thus, at the cellular and synaptic levels, a heightened level of inhibition exists from the end of the fourth to the end of the fifth postnatal week in the rat visual cortex and towards the end of the second postnatal week in the rat respiratory system [22,47]. They coincide temporally with the peak of the critical period in each system.

(b) . Period of reduced brain-derived neurotrophic factor expression

What causes such a surge in inhibition during the critical period? The prevailing dogma is that it is fuelled by a rise in brain-derived neurotrophic factor (BDNF) [4,34,48]. BDNF mRNA levels in the visual cortex reportedly rise soon after eye opening and plateau thereafter into adulthood [49], and BDNF immunoreactivity supposedly ‘peaked’ during the critical period [50]. Moreover, over-expressing BDNF in transgenic mice causes an earlier onset and closure of the critical period [48]. The apparent temporal correspondence between heightened inhibition and ‘peak’ expression of BDNF led to the reasonable conclusion that a rise in BDNF during the critical period is necessary for the maturation of GABAergic inhibition [34,48].

However, a different conclusion was reached recently by Zhang et al. [22] when they measured the immunoreactivity of BDNF and its TrkB receptors in single neurons of the rat visual cortex, daily, from P14 to P36. They noted that, against a gradual rise with age, both BDNF and TrkB expressions abruptly fall at P28–P33 (figure 2a), the exact period of rise in inhibition [28]. Why was this not observed previously by others? It turns out that Rossi et al. [50] focused only on P5, 10, 15, 20 and the adult (their fig. 2) and missed the interval between P20 and adulthood entirely. Bozzi et al. [49] showed a fall in BDNF mRNA level at P30 (their fig. 2) but the error bars may be too large to reach significance. Huang et al. [48] reported a weekly rise in BDNF mRNA levels from P2 to P35 but showed a fall at P28 in their transgenic mice (their fig. 1d) that was not significant, perhaps owing to overlapping error bars.

Figure 2.

Figure 2.

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Optical densitometric analysis of BDNF immunoreactivity in single neurons of (a) layers II to VI of the rat visual cortex, daily, from P14 toP36 (modified from [22]) and (b) a respiratory nucleus in the rat brain stem from P0 to P21 (modified from [51]). Circled regions highlight the critical periods when the level of BDNF is significantly reduced. **p < 0.01; *p < 0.05 (Tukey's test). (Online version in colour.)

To address the relationship between BDNF and inhibition further, Zhang et al. [22] administered a TrkB agonist in vivo during the period of heightened inhibition (P29–P30). It significantly reduces the normally elevated sIPSCs in the visual cortex. Conversely, a TrkB antagonist enhances the inhibition.

In respiratory nuclei, BDNF/TrkB immunoreactivity is relatively high from P0 to P11 but falls significantly at P12–P13 (when inhibition dominates) before returning to P11 levels at P14 and thereafter (figure 2b) [51,52]. Such a fall is not detected in a non-respiratory nucleus [51]. BDNF and TrkB mRNA levels also plunge in a respiratory nucleus at P12–P13 [52]. Electrophysiologically, BDNF applied to respiratory nuclei at P12–P13 significantly reduces the normally elevated sIPSCs, an effect reversible with a TrkB antagonist [52]. In vivo a TrkB agonist also downregulates sIPSCs at P12–P13, but a TrkB antagonist significantly increases them [53]. These responses are not seen before or after this period.

Clearly, the action of BDNF/TrkB is to suppress, rather than accentuate, inhibition. The fact that their levels are down at P28–P33/34 in the visual cortex and at P12–P13 in respiratory nuclei explains, at least in part, the upsurge of inhibition during these critical periods.

How unique is this effect of BDNF on inhibition? In several brain regions, BDNF enhances glutamatergic neurotransmission and attenuates GABAergic ones [54–57]. In the hippocampus, BDNF's action on GABAAR-mediated currents changes from potentiation to suppression during postnatal maturation of pyramidal neurons [58]. Wardle & Poo [57] found that BDNF has differential effects on different cell types. For glutamatergic neurons, BDNF increases the amplitude of postsynaptic currents (EPSCs) but decreases slightly that of IPSCs by reducing presynaptically evoked GABA release. For GABAergic neurons, BDNF modifies their IPSC amplitudes by downregulating their postsynaptic KCC2 (a Cl− exporter, which favours hyperpolarization), thereby decreasing the efficacy of inhibition [57,59]. Notably, the switch in dominance from the Cl− importer (NKCC1, which favours depolarization) to KCC2 occurs in both the visual cortex [22] and the respiratory system [60] close to the start of their respective critical period. Again, reduced BDNF expression would facilitate KCC2 action and strengthen the inhibitory effect of GABAergic neurotransmission.

BDNF is known to play an important role in neuronal growth and differentiation, survival, synapse formation and plasticity [61]. In the respiratory system, BDNF/TrkB signalling is essential for the development and control of normal breathing [62], and knocking out the Bdnf gene leads to severe respiratory dysfunction, including death [63]. Before the critical period, BDNF probably enhances the growth of excitatory synapses to establish a genetically determined synaptic network. It probably also facilitates initial GABAergic axonal growth when the latter mediates excitatory depolarizing currents. The parallel increase in GABAARα1 and BDNF expressions from P14 to P27 [22] is consistent with this premise. However, maturation to a fully inhibitory hyperpolarizing GABAergic (or glycinergic) transmission requires a transient downregulation of BDNF and glutamatergic receptor expressions [22,51]. In transgenic, BDNF-overexpressed mice [48], BDNF probably hastens neuronal growth and synapse formation, but the precise timing of their critical period is unclear. A day-to-day developmental study would clarify this issue.

With regard to excitation, BDNF increases glutamate release from presynaptic terminals and potentiates excitation [64]. A reciprocal relationship exists between BDNF and neuronal activity, such that BDNF modulates synaptic transmission, but its own synthesis and secretion are activity dependent [65]. BDNF induces long-term potentiation in dendrites that contain N-methyl-D-aspartate receptors (NMDARs), thereby functioning synergistically with neuronal activity to promote synaptic plasticity [66]. Activated synaptic NMDARs, in turn, stimulate BDNF transcription [67]. During development, intracortical infusion of immunoglobulin to TrkB receptors blocks the endogenous ligand and prevents ocular dominance column formation, suggesting that geniculocortical axons may compete for BDNF when establishing eye-specific columns [68]. The fact that BDNF enhances excitation and weakens inhibition leads to the third basic mechanism of the critical period.

(c) . Period of synaptic imbalance: heightened inhibition is not matched by increased, but by suppressed excitation

No doubt, a substantial increase in GABAergic inhibition is necessary for eliciting and maintaining the critical period, but is it also ‘sufficient’ as once claimed [34, pp. 879, 887; 69, pp. 51, 56]? Do ‘excitatory and inhibitory circuit elements reach an optimal balance once in life during which plasticity may occur’ [32, p. 184]? From a homeostatic viewpoint, heightened inhibition should be accompanied by a parallel increase in excitation. Indeed, the expression of NMDAR was thought to be high during the critical period [34,70].

However, the day-to-day studies revealed a sudden fall in the amplitudes and frequencies of sEPSCs at the precise time when the sIPSCs are sharply increased, i.e. P28–P33/34 in the visual cortex (figure 1c,d) [22] and P12–13 in the respiratory system (figure 1g,h) [36]. Neurochemically, a significant reduction in the expressions of excitatory neurotransmitters and receptors (glutamate, NMDAR1/NR1/GluN1 and AMPAR1/GluA1) is noted in both the visual cortex and the respiratory system during the period of heightened inhibition and not before or after [22,39,40]. The evoked EPSC to IPSC (E/I) ratio in the visual cortex is also the lowest at P28 (during the critical period) when compared to before (P18 and P25) or after (P36) this period [22].

Thus, rather than an ‘excitatory-inhibitory circuit balance’ [28], it is a state of synaptic imbalance that triggers and characterizes the critical period. Why was this not found previously? Kumar et al. [71] assumed that glutamatergic receptors have reached adult levels by P20–25, so they did not examine the period from P25 to adulthood. Cao et al. [72] did show a fall in immuno-labelling for NR1 (GluN1) at P30 in the rat visual cortex (their fig. 7b). However, comparisons among five time points did not reach significance, perhaps owing to an inadequate N.

Administering a TrkB agonist in vivo during the respective critical period significantly increases sEPSCs in the visual cortex [22] and respiratory nuclei [53]. Conversely, a TrkB antagonist yields the opposite effect. These changes contrast those of sIPSCs (see §4b) and are not observed before or after the critical periods [22,53]. Neurochemically, a TrkB agonist increases the expression of GluN1 but decreases that of GABAARα1 during the critical period, whereas a TrkB antagonist leads to the converse [22]. Thus, exogenous BDNF partially reverses the synaptic imbalance, but blocking BDNF signalling accentuates the imbalance during the critical period in both the visual cortex and the respiratory system [22,52,53].

Reduced excitation should also lower energy demand, and indeed, the level of a metabolic indicator of neuronal activity, cytochrome oxidase, falls in temporal coincidence with the decrease in excitation during the respective critical periods in the visual cortex and the respiratory system [22,73]. Such changes are also in keeping with BDNF's normal role in stimulating energy metabolism by increasing glucose use/transport and enhancing protein synthesis [74].

5. Effect of perturbation during the critical period

As noted in the Introduction, numerous studies have chronicled marked morphological, physiological and behavioural plasticity in response to environmental or experimental perturbations during the critical period that will not be repeated here. The main effect of monocular deprivation is a shift in ocular dominance and a decrease in visual acuity [1,18,21,75]. Cortical pyramidal neurons initially respond less to the closed eye owing to enhanced inhibitory feedback, but subsequently they are disinhibited by the suppression of inhibitory interneurons, resulting in increased response to the open eye, indicating a homeostatic mechanism [76–79]. Thalamic GABAARα1-mediated inhibition also contributes to cortical plasticity [43]. These studies focus mainly on layers II/III/IV neurons before P28/29 (i.e. before the peak of the critical period) [77–79].

Zhang et al. [22] studied layer V pyramidal neurons and found that monocular deprivation for 4 days during the height of synaptic imbalance (P28–32) induces significant reductions in both sEPSCs and sIPSCs not observed before (P19–22) or after (P35–38) this period (except for a fall in sEPSCs at P23). A significant decrease in the expressions of GluN1, GABAARα1 and cytochrome oxidase is also detected in deprived neurons during, but not before or after, the critical period [22].

Regarding BDNF, dark rearing or monocular impulse blockade reduces its mRNA in the visual cortex [80]. Likewise, two weeks or one month of monocular deprivation downregulates its mRNA and immunoreactivity [49,50]. However, as little as 4 days of lid suture during the critical period suppresses the protein expressions of both BDNF and TrkB, indicating their activity dependency [22]. Exogenous TrkB agonist administered during the critical period enhances excitation but suppresses inhibition in both non-deprived and deprived neurons beyond levels of their non-treated controls [22]. On the other hand, a TrkB antagonist has the opposite effect. Thus, BDNF exerts a comparable impact on normal and visually deprived cortical neurons.

In the respiratory system, 5 min of acute hypoxia in vivo induces the weakest response at P12–13, the critical period [37]. In brain stem slices, acute hypoxia at P12–13 also generates the lowest sEPSCs but enhances sIPSCs when compared to those before or after this period [53]. Thus, acute hypoxia suppresses excitation and releases inhibition in respiratory neurons, but monocular deprivation for 4 days subdues both excitation and inhibition in cortical neurons.

Outside the critical period, sudden and/or drastic alterations in the excitatory-inhibitory balance can trigger the second period of plasticity. Examples include GABA release from transplanted embryonic GABAergic neurons or reducing cortical inhibition with fluoxetine, picrotoxin or a GAD inhibitor [81–83].

6. Is the critical period necessary?

The negative aspect of the critical period begs the question: why has this period persisted in development and through evolution? Is the critical period really necessary?

In both the visual cortex and the respiratory system, excitatory synapses develop and mature earlier than inhibitory ones [36,38]. This ensures the launching of a crucial synaptic network connecting essential participants. In the visual cortex (and probably other cortical areas), innately determined thalamocortical connections and basic functional architecture are established first, guided by spontaneous neural activity independent of visual input [25], and GABAergic transmission is initially excitatory [84]. However, the refinement of neuronal properties, receptive field characteristics and synaptic connections require the growth and maturation of inhibitory synapses guided by environmental cues. Likewise, refinement of respiratory neuronal properties would require inhibitory adjustments [16,47]. To enable inhibitory synapses to flourish, the systems require a transient suppression of excitation by downregulating BDNF and glutamatergic synapses. However, such adjustments render these systems less stable and more vulnerable to external perturbations. This period must be brief in the respiratory system to minimize possible threats to survival, but it can be prolonged (as in the visual cortex) when stressors are not life-threatening. Nonetheless, the critical period is a necessary rite of passage for many, if not all, systems to transition from immaturity to maturity.

After the critical period, the systems mature to a state of relative excitatory-inhibitory (E/I) balance, aided by BDNF and probably other factors. If the normal E/I balance is never achieved, neurological disorders such as schizophrenia, Rett syndrome or autism can result [85–87].

Is there any evolutionary advantage to having a critical period? It is true that the critical period is a time when sensory experience is required to maintain an intrinsically determined circuitry. However, synaptic instability arising from synaptic imbalance during the critical period also primes the system for Hebbian modificatons in response to the strongest afferent inputs [26]. For the individual animal, the critical period allows its nervous system to fine tune its adjustments to a new environment, which, if persists, will cause subsequent generations to adapt optimally to that environment. Darwin's theory [88] of natural selection necessitates a superior adaptability to one's environment. The possibility to adapt rapidly during the critical period through generations would be a distinct advantage. In this sense, the critical period is not only beneficial, but can be vital, to the perpetuation of that species.

7. Is there a master regulator of the critical period?

No doubt, the formation of a critical period is multifactorial, with many players, feedforward and feedback loops, signalling cascades and interactions [2,4,5,47,89]. However, whether there is a master regulator with broad influence is currently unknown. BDNF certainly plays an important role. Two other candidates deserve consideration. (i) Pituitary adenylate cyclase-activating polypeptide (PACAP) in the hypothalamus [90]. It is implicated in neural development, modulation, protection, neurotransmission, metabolic homeostasis and transcriptional processes [91,92]. In the respiratory system, PACAP stimulates breathing and without it, mice die during the second postnatal week [93], the critical period of respiratory development. In normal rats, PACAP immunoreactivity is significantly reduced in multiple respiratory nuclei during the critical period [94]. PACAP also stimulates BDNF expression by enhancing synaptic NMDAR currents and modulating synaptic plasticity [95]. The concurrent downregulation of NMDAR1, BDNF and PACAP in respiratory nuclei during the critical period suggests a coordinated mechanism in enabling synaptic imbalance. Whether PACAP plays a similar role in the visual cortex is unknown at present. (ii) Thyroid hormone. It is essential for neurogenesis, neuronal differentiation, myelination and synaptogenesis [96]. It is also involved in energy metabolism, GABAergic synaptic development and BDNF regulation [97,98] and is recently proposed as a key regulatory factor for the critical period [99]. Other candidates will undoubtedly be uncovered in the future. Most likely, interactions among major regulators, rather than a single regulator, hold the key.

8. What are the basic principles underlying postnatal neuronal development?

In summary, a few insights on the basic principles of neuronal development can be gleaned (figure 3).

  • (i)

    Postnatal neuronal development does not follow a straight trajectory. Excitatory synapses are developed before inhibitory ones to establish the innately determined connections, neuronal organization and the synaptic network. This stage of excitatory development (including glutamatergic and depolarizing GABAergic ones) requires BDNF (and probably other factors).

  • (ii)

    Excitatory development gives way to the growth and maturation of inhibitory synapses to fine-tune neuronal properties and connections in response to the animal's and the system's environment. Inhibitory dominance is facilitated by a transient downregulation of BDNF/TrkB and a suppression of excitatory synapses, resulting in a state of synaptic imbalance, the critical period. Such an imbalance may render the animal more vulnerable to extrinsic stressors.

  • (iii)

    The critical period is necessary so that neurons can mould their structures and functions and adapt optimally to their environment. This is a time of experience-dependent plasticity. It has to be brief in the respiratory system to limit possible life-threatening responses, but it can be longer in the visual cortex. It can be accelerated, delayed or prolonged, but it is not easily eliminated unless key factors are removed or insults are induced genetically, pathologically or experimentally.

  • (iv)

    The critical period is followed by a relatively stable state of excitatory-inhibitory balance, when the system has reached its full maturity, and BDNF is again crucial. Abnormal imbalance in the adult can trigger further adjustments known as adult plasticity. On the other hand, the inability to reach such a synaptic balance can result in neurological disorders.

Figure 3.

Figure 3.

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Summary diagram of major developmental events before, during and after the critical period. The critical period is marked by synaptic imbalance, with enhanced inhibition and suppressed excitation, aided by reduced BDNF/TrkB expression. The imbalance can be reversed or accentuated by TrkB agonist or antagonist, respectively.

Supplementary Material

Click here for additional data file. (382.4KB, pdf)

Acknowledgement

I am indebted to many talented students and postdocs who contributed greatly to unravelling the critical period.

Data accessibility

This article has no additional data.

Competing interests

I declare I have no competing interests.

Funding

I received no funding for this review.

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