Brain-derived neurotrophic factor (BDNF) reverses the effects of rapid eye movement sleep deprivation (REMSD) on developmentally regulated, long-term potentiation (LTP) in visual cortex slices

Abstract

Work in this laboratory demonstrated a role for rapid eye movement sleep (REMS) in critical period (CP), postnatal days (P) 17–30, synaptic plasticity in visual cortex. Studies in adolescent rats showed that REMS deprivation (REMSD) reinitiates a developmentally regulated form of synaptic plasticity that otherwise is observed only in CP animals. Subsequent work added that REMSD affects inhibitory mechanisms that are thought to be involved in terminating the CP. Neurotrophins are implicated in the synaptic plasticity that underlies CP maturation and also final closure of the CP in visual cortex. Expression of brain-derived neurotrophic factor (BDNF) is dependent upon neuronal activity, and REMSD may block BDNF expression. We propose that REMS contributes to the maturation of visual cortex through regulation of BDNF expression and consequent, downstream increase in cortical inhibitory tone. In this study, osmotic minipumps delivered BDNF into visual cortex on one side of brain. The opposite hemisphere was not implanted and served as an internal control. We tested the hypothesis that BDNF is blocked by REMSD in late-adolescent rats and investigated whether replacing BDNF prevents induction of LTPWM-III by theta burst stimulation (TBS). We also assessed relative inhibitory tone in visual cortex with paired-pulse stimulation (PPS) in animals that were similarly REMSD- and BDNF-infused. After REMSD, both hemispheres were prepared in parallel for in vitro synaptic plasticity studies (LTPWM-III or PPS). In visual cortex of REMSD rats on the side receiving BDNF infusions (8 of 8 animals), TBS consistently failed to induce LTPWM-III. In contrast, LTPWM-III was obtained (5 of 5 animals) in the matched, non-infused hemisphere, as expected in rats of this age. REMSD animals that were unilaterally infused with saline produced LTPWM-III in both hemispheres. PPS studies in another group of REMSD animals that were unilaterally BDNF-infused displayed age-appropriate inhibition of the second response on the BDNF-infused side (5/5), whereas on the non-infused side facilitation was observed (3/3). Intracortical infusion of BDNF in REMSD adolescent rats appears to restore neurochemical processes necessary for termination of the CP for developmentally regulated synaptic plasticity in visual cortex. The results suggest that REMSD blocks BDNF expression and also maturation of inhibitory processes in adolescent visual cortex. These data support REMS’ function in brain development.

Introduction

The brain is most plastic during the developmental period. For example, during an early-life critical period (CP) of development in the visual system, typically spanning postnatal days P17–P30, synaptic connectivity is strongly affected by sensory input, whereas later in life this plasticity is available only under a limited set of conditions (c.f., [19]). The classical experiments demonstrating the so called “ocular dominance shift” revealed that when vision in one eye is blocked for a short time in CP animals, visual system synaptic connections are remodeled and a response bias, or shift toward input from the open eye, is observed [18]. Blocking visual input to one eye in adults does not typically produce shifts in ocular dominance (but see [19]). Despite an expanding literature describing the mechanisms underlying this ocular dominance shift, our understanding is not complete. Many of the known mechanisms have been reported, however, to have commonalities with certain forms of experimentally produced, in vitro models of synaptic plasticity such as long-term potentiation (LTP), long-term depression (LTD), and paired-pulse stimulation (PPS) [16], [31]. Several in vitro forms of LTP can be produced at synapses in visual cortex [3], [20]. An age-dependent type [21] can usually be evoked only during the developmental CP of the visual system [21]. This form of LTP (LTPWM-III) is produced in visual cortex layers II/III by fast frequency, theta-burst stimulation (TBS) of the white matter (WM) below V1 that carries visual information from lateral geniculate nucleus (LGN) to cortical processing areas. Shifts in LTPWM-III production and ocular dominance following arrested visual input during the CP appear to depend upon NMDA receptors [2], metabotropic glutamate receptors [39], and several neurotrophic factors, including brain-derived neurotrophic factor (BDNF) [17], [22], [26].

After P30, WM stimulation alone seldom evokes LTPWM-III [21], [30]. Rearing in complete darkness extends the usual duration of the CP for production of LTPWM-III [21]. Studies in our laboratory demonstrated that suppression of rapid eye movement sleep (REMS), starting just before the end of the CP and lasting up to 10 days, promotes a similar extension of the CP for LTPWM-III [36]. We subsequently found that REMS deprivation (REMSD), initiated shortly after the expected end-point of the CP in early adolescent rats (P35–45), seems to reinstate the conditions for producing LTPWM-III [35]. These findings and the dark-rearing studies from Bear's laboratory [21] suggest that endogenous neural activation during REMS as well as exogenous sensory stimulation of visual system contribute to configuring synaptic connectivity in the developing brain despite acting in different circadian phases. REMS-generated activation of the visual system impacts receptors on many of the same LGN cells that also receive inputs from retinal ganglion cells [9], [32]. Accordingly, sequential activation of visual neurons by waking sensory input and REMS-generated activity appears necessary for normal termination of CP synaptic plasticity. Conversely, removal of either of these sources of activation is sufficient to delay the end of the CP [21], [36].

Although the specific mechanisms that operate to terminate the CP for LTPWM-III are incompletely established, neurotrophic factors appear to be critical to visual system development [17], [33]. Though not the sole regulator of synaptic plasticity, BDNF and its tyrosine kinase receptors likely influence synaptic plasticity in developing visual cortex [5]. When the postnatal rise of BDNF was accelerated in transgenic mice, precocious development of visual acuity and earlier termination of the CP for ocular-dominance was observed [14], [17]. These mice additionally exhibit accelerated maturation of cortical gamma-aminobutyric acid (GABAergic) inhibition and age-dependent decline of cortical LTPWM-III [14], [17]. Recent data strengthen BDNF's influence on the GABAergic system in visual cortex during the CP to bring about a developmental shift from a largely excitatory initial effect to a later, almost exclusively inhibitory, effect [14], [17], [25]. BDNF facilitates developing GABA inhibitory processes, thereby contributing to closure of the CP [15], [17].

Other lines of evidence suggest that BDNF also plays a key role in maturation of GABAergic mechanisms and closure of the CP in visual cortex. Visual activity differentially modulates BNDF mRNA expression in visual cortex, which is low in dark-reared rats and elevates after exposure to light [33]. GABAergic transmission in visual cortex slices from dark-reared, CP rats is threefold lower than in normally reared animals [28]. Further, mice lacking the enzyme to synthesize an isoform of a GABA synthetic enzyme, glutamic acid decarboxylase (GAD65), show unremitting delay of CP onset, but injection of GABAergic agonists initiates the CP [11].

We have observed that REMSD alters the balance between inhibitory and excitatory mechanisms in the developing, CP visual cortex [34]. Taken together with REMSD's extension of the period in which LTPWM-III can be produced [36], we hypothesized that REMS promotes development of inhibitory processes in visual cortex. We examine here whether REMSD affects developmental synaptic plasticity in visual cortex via a BDNF pathway. We explore this possibility by infusing BDNF into REMSD, adolescent rat visual cortex. We then tested for LTPWM-III in both the infused and non-infused sides of brain. The influence of REMSD and BDNF on inhibitory mechanisms in the adolescent rat is gauged by the relative maturity of inhibitory mechanisms in visual cortex.