Forebrain overexpression of α-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption

Abstract

Transgenic (Tg) mouse models of Parkinson's disease (PD) generated to date have primarily been designed to overexpress human alpha-synuclein (α-syn) to recapitulate PD-like motor impairments as well as PD-like nigro-striatal degeneration and α-syn pathology. However, cognitive impairments and cortical α-syn pathology also are common in PD patients. To model these features of PD, we created forebrain-specific conditional Tg mice that overexpress human wild type (WT) or A53T mutant α-syn. Here we show that both WT and A53T mutant α-syn lead to massive degeneration of postmitotic neurons in the hippocampal dentate gyrus (DG) during postnatal development, with hippocampal synapse loss as evidenced by reduced levels of pre-and postsynaptic markers. However, when mutant and WT α-syn expression was repressed until the Tg mice were mature postnatally and then induced for several months, no hippocampal neuron loss was observed. These data imply that developing neurons are more vulnerable to degenerate than mature neurons as a consequence of forebrain WT and mutant α-syn overexpression.

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

“…Finally, the threefold overexpression of h-αSyn WT was sufficient to trigger memory deficits in 7-mo-old transgenic (Tg)I2.2 mice in the absence of αSyn cytopathology (18). At a cellular level, the elevation of IC monomeric αSyn observed in AD coincided with selective reductions in two presynaptic proteins, synapsin and complexin, and with a perturbed colocalization of αSyn and synapsins within presynaptic vesicles (18), in agreement with previous reports (8,19,20). These observations therefore suggested a possible connection between the dysregulation of αSyn expression and alterations in presynaptic vesicle composition and release.…”

Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice

“…Mice showed neuronal expression predominantly, albeit not exclusively, in forebrain structures, consistent with the properties of the Camk2a promoter (21,22). To demonstrate the regional differences in TDP-43 expression, protein lysates were analyzed using antibodies specific for hTDP-43 and antibodies recognizing both hTDP-43 and endogenous mTDP-43 (h+mTDP-43).…”

“…Mice were perfused and tissues were processed for IHC and IF as described (21). In general, the left hemisphere was dissected into cortex, hippocampus, cerebellum, olfactory bulb, and the rest of the tissue (subcortical structures, brainstem) and frozen at -80°C until used for biochemical analysis.…”

“…In general, the left hemisphere was dissected into cortex, hippocampus, cerebellum, olfactory bulb, and the rest of the tissue (subcortical structures, brainstem) and frozen at -80°C until used for biochemical analysis. The right hemisphere and spinal cord sections were immersed in neutral buffered formalin (NBF) (Fisher Scientific) and processed for IHC (21,35).…”

“…To create conditional mouse models of TDP-43 proteinopathies, we generated Tg mice expressing hTDP-43-ΔNLS and its control counterpart hTDP-43-WT using CaMK2α promoter elements to drive tet-off tTA (Camk2a-tTA) and a tetracycline responsive promoter to drive hTDP-43 expression (tetO-hTDP-43; Figure 1A) (21)(22)(23). Bigenic mice (Camk2a-tTA x tetO-hTDP-43) were maintained on Doxycycline (Dox) to inhibit transgene expression until 28 days of age when they were switched to a Dox-free diet and sacrificed at the designated time points off Dox ( Figure 1B).…”