Postsynaptic TrkB signaling has distinct roles in spine maintenance in adult visual cortex and hippocampus

Abstract

In adult primary visual cortex (V1), dendritic spines are more persistent than during development. Brain-derived neurotrophic factor (BDNF) increases synaptic strength, and its levels rise during cortical development. We therefore asked whether postsynaptic BDNF signaling through its receptor TrkB regulates spine persistence in adult V1. This question has been difficult to address because most methods used to alter TrkB signaling in vivo affect cortical development or cannot distinguish between pre-and postsynaptic mechanisms. We circumvented these problems by employing transgenic mice expressing a dominant negative TrkB-EGFP fusion protein in sparse pyramidal neurons of the adult neocortex and hippocampus, producing a Golgi-staining-like pattern. In adult V1, expression of dominant negative TrkB-EGFP resulted in reduced mushroom spine maintenance and synaptic efficacy, accompanied by an increase in long and thin spines and filopodia. In contrast, mushroom spine maintenance was unaffected in CA1, indicating that TrkB plays fundamentally different roles in structural plasticity in these brain areas.adult cortical plasticity ͉ BDNF signaling ͉ synapse stability ͉ transgenic mice D uring development, synapse formation and elimination are regulated by molecular cues, spontaneous activity, and experience (1, 2). Most glutamatergic synapses on excitatory neurons are situated on dendritic spines. Live imaging of neurons expressing GFP has provided important information on the dynamics of spine formation and maintenance (3-8). Filopodia are short-lived fingershaped protrusions and believed to be precursors of dendritic spines (9, 10). Newly formed spines are often thin or long and appear and disappear within days. Some mature into mushroom or stubby spines, which are more stable and often persist for months (7,8). There are strong correlations between spine size, spine persistence, synaptic efficacy, and the number of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) at the postsynaptic density (8,11,12). With development and aging of the cortex, there is a shift toward larger and more persistent spine types (3,7,13).Spine dynamics are influenced by plasticity. Long-term potentiation in hippocampus is associated with an increase in spine size (14) and spine formation (15), whereas term depression is associated with spine elimination (16). Interestingly, reducing synaptic input results in an increase in spine numbers, probably due to homeostatic mechanisms (17)(18)(19).Ocular dominance plasticity in V1 is associated with initial pruning and later formation and stabilization of spines (20,21) and occurs predominantly during a critical period of development. Maturation of the extracellular matrix is a major factor in ending the critical period, probably by increasing spine and axon stability (20)(21)(22) BDNF signaling through TrkB receptors is a key player in visual plasticity (23,24). It drives the development of inhibitory innervation, an important factor in ocular dominance plasticity (25,26). BDNF is...

Selective Deletion ofBdnfin the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity

“…Exogenous BDNF rapidly activates neurons in hypothalamic appetite-regulating centers Because BDNF can be secreted from dendrites or axonal terminals, it can act presynaptically or postsynaptically (Gottschalk et al, 1998;Xu et al, 2000;Chakravarthy et al, 2006). There are also examples of this neurotrophin acting in an autocrine manner in the literature (Barnabe-Heider and Miller, 2003;Kim et al, 2004).…”

Contrast gain control and cortical TrkB signaling shape visual acuity

“…Mice with a Cre-dependent TrkB.T1-EGFP transgene (TLT-817) were described previously 16 . TrkB.T1-EGFP transgenic animals were crossed to animals from the G35-3-Cre line 20 .…”

“…This was achieved by crossing mice carrying a Cre-dependent TrkB.T1-EGFP-transgene under the control of the Thy-1 promoter 16 with G35-3 Cre-recombinase transgenic animals 20 ( Supplementary Fig. 1).…”

“…Moreover, transgenic mice overexpressing BDNF in the forebrain show a faster rise of cortical acuity 6 even when reared in darkness 13 . Although there is a wealth of data on the involvement of BDNF and its main receptor TrkB in neuronal development 14 , synaptic efficacy 15 , -morphology 16 and -plasticity 17,18 , it has remained unknown how BDNF promotes visual acuity at the coding level and whether BDNF signaling plays a role in acuity in the mature cortex. For these reasons we studied visual acuity in adult transgenic mice where, after normal development is completed, cortical TrkB/BDNF signaling is impaired.…”

Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells

“…The importance of TrkB and/or BDNF for neuronal development differs between brain regions (Klein et al, 1993;Chakravarthy et al, 2006). From the analysis of mutant mice it is known that the axonal and dendritic arborizations of granule and Purkinje cells (PCs) are reduced by ~20% in the absence of TrkB (Minichiello and Klein, 1996;Rico et al, 2002) and even more in the absence of BDNF (Schwartz et al, 1997;Carter et al, 2002).…”