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
Highlights
► Intracortical infusion of BDNF reverses synaptic plasticity effects of adolescent REMS deprivation. ► REMS contributes to the effects of BDNF activation on closure of the critical period in visual cortex. ► Adolescent REMS deprivation affects the development of visual cortical inhibitory mechanisms.
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.
Section snippets
Methods
All procedures were approved by the University of Mississippi Medical Center (UMMC) IACUC and comply with regulatory guidelines. Long–Evans Hooded rats (P28) from timed-pregnant dams (Harland Laboratories, Inc.) were housed in the animal facilities for one week. Each animal was then implanted with a cannula aimed at the binocular area of visual cortex on the left side of brain (A: 2.0, L: 2.0, and H: 1.0–2.0 mm below skull [29]). The cannula was connected to an osmotic minipump (Alzet, Model
Results
As expected in adolescent rats after a period of REMSD [35], TBS of WM on the non-infused side of cortex uniformly induced LTPWM-III (5/5, Fig. 1A). In contrast, induction of LTPWM-III failed in hemispheres receiving BDNF infusions (8/8 animals, Fig. 1B). As such, BDNF-infused visual cortex in REMSD, adolescent rats showed significantly less LTPWM-III production (no post-TBS increase in response amplitude) than observed in the same animals’ non-infused cortex (Fishers exact t-test, p < 0.001). In
Discussion
Infusion of BDNF for 24 h was sufficient to antagonize the effects of three days of REMSD on LTPWM-III production in post-CP adolescent rats. As such, BDNF-infusion appears to reverse REMSD-induced reestablishment of the CP for developmental synaptic plasticity in adolescent rats [35]. The expected action of inhibitory mechanisms considered partly responsible for closure of the CP at this age [31] seems to be reinitiated in REMSD adolescent rats by BDNF infusion. The specificity of BDNF for this
Acknowledgments
Research supported by: NIH/NINDS NS-31720 and UMMC Intramural Research Support Program.
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