Guthrie, Kathleen

The causes of autism spectrum disorder (ASD) are not all known, but it is suspected that the serotonin transporter (SERT) plays an important role for some subjects with ASD. Mutations in the SLC6A4 gene, that encodes SERT, including the Ala56 mutation (Gly56Ala), have been found in some autism patients. This mutation makes the transporter more active and reduces the probability of serotonergic neurotransmission in the brain, which is linked to behavioral changes that are associated with core domain deficits of ASD 1.
Depression also has been linked to decreases in the availability of serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system (CNS), and is associated with reduced hippocampal neurogenesis. Selective serotonin reuptake inhibitors (SSRIs), drugs used to block SERTs, are used to treat depression and/or anxiety by inhibiting SERT to increase synaptic 5-HT levels.

Olfactory Granule cells (GCs) are a population of inhibitory interneurons
responsible for maintaining normal olfactory bulb (OB) function and circuitry. Through
dendrodendritic synapses with the OBs projection neurons, the GCs regulate information
sent to the olfactory cortices. Throughout adulthood, GCs continue to integrate into the OB
and contribute to olfactory circuitry. However, only ~50% will integrate and survive longterm.
Factors aiding in the survival and morphological development of these neurons are
still being explored. The neurotrophin brain-derived neurotrophic factor (BDNF) aids in
the survival and dendritic spine maturation/maintenance in several populations of CNS
neurons. Investigators show that increasing BDNF in the adult-rodent SVZ stimulates
proliferation and increases numbers of new OB GCs. However, attempts to replicate these
experiments failed to find that BDNF affects proliferation or survival of adult-born granule
cells (abGCs). BDNFs regulation of dendritic spines in the CNS is well characterized. In
the OB, absence of BDNF’s receptor on abGCs hinders normal spine development and demonstrates a role for BDNF /TrkB signaling in abGCs development. In this study, we
use transgenic mice over-expressing endogenous BDNF in the OB (TgBDNF) to determine
how sustained increased in BDNF affect the morphology of olfactory GCs and the survival
and development of abGCs. Using protein assays, we discovered that TgBDNF mice have
higher BDNF protein levels in their OB. We employed a Golgi-cox staining technique to
show that increased BDNF expression leads to an increase in dendritic spines, mainly the
mature, headed-type spine on OB GCs. With cell birth-dating using 5-bromo-2’-
deoxyuridine (BrdU), immunofluorescent cell markers, TUNEL staining and confocal
microscopy, we demonstrate that over-expression of BDNF in the OB does not increase
survival of abGCs or reduce cell death in the GC population. Using virally labeled abGCs,
we concluded that abGCs in TgBDNF mice had similar integration patterns compared to
wild-type (WT) mice, but maintained increases in apical headed-type spine density from
12 to 60 days PI. The evidence combined demonstrates that although increased BDNF does
not promote cell survival, BDNF modifies GC morphology and abGC development
through its regulation of dendritic spine development, maturation and maintenance in vivo.