Pathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb

Abstract

Although the role of noxious α-synuclein (α-SYN) in the degeneration of midbrain dopaminergic neurons and associated motor deficits of Parkinson’s disease is recognized, its impact on non-motor brain circuits and related symptoms remains elusive. Through combining in vivo two-photon imaging with time-coded labelling of neurons in the olfactory bulb of A30P α-SYN transgenic mice, we show impaired growth and branching of dendrites of adult-born granule cells (GCs), with reduced gain and plasticity of dendritic spines. The spine impairments are especially pronounced during the critical phase of integration of new neurons into existing circuits. Functionally, retarded dendritic expansion translates into reduced electrical capacitance with enhanced intrinsic excitability and responsiveness of GCs to depolarizing inputs, while the spine loss correlates with decreased frequency of AMPA-mediated miniature EPSCs. Changes described here are expected to interfere with the functional integration and survival of new GCs into bulbar networks, contributing towards olfactory deficits and related behavioural impairments.

Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development

“…In terms of neuronal function, we found that the reduced spine density may be associated with alterations in mPSC frequency, amplitude and rise time. Consistent with our results, a recent study using the A30P α-SYN transgenic mice displayed impairments in dendritic branching and spine density, corresponding with decreased mPSC frequency and increased mPSC amplitude 40 . Other studies have also demonstrated a positive correlation between spine loss and decreased mPSC frequency, suggesting that synapse number is a strong determinant of neuronal transmission 41 .…”

Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

“…Previous publications report contrasting findings on the effects of aSyn on neurite outgrowth. Liu et al 47 reported that aSyn promotes neurite growth in cultured primary neurons, whereas other investigators 48 , 49 , 50 have shown a negative impact of aSyn on neurite outgrowth. A fundamental difference between these studies is the choice of the cellular models used to investigate the effects of aSyn.…”

Seeding and transgenic overexpression of alpha‐synuclein triggers dendritic spine pathology in the neocortex

“…In contrast, another study failed to detect striatal spine loss in A53T mice, despite a decrease in the number of SNpc neurons (Oaks et al , ). α‐syn was also demonstrated to have negative impact on newly generated neurons of the hippocampus (Winner et al , ) and the olfactory bulb (Neuner et al , ), particularly on their dendrite outgrowth and spine development.…”

“…Dendritic spines are small protrusions from the dendritic shaft which are highly regulated and have been shown to be altered in several neurological disorders including neurodegenerative diseases (Fiala et al , ; Penzes et al , ; Murmu et al , ). Various studies in the field of α‐syn‐related disorders have addressed the impairment of dendritic spines in brain areas like the striatum (McNeill et al , ; Day et al , ; Zaja‐Milatovic et al , ; Finkelstein et al , ), the hippocampus (Winner et al , ), the olfactory bulb (Neuner et al , ), and naturally the substantia nigra (Patt et al , ). However, chronic effects of cortical α‐syn have not been studied extensively, even though it is becoming more and more evident that the cortical involvement in the pathophysiology of PD and DLB cannot be neglected.…”