Cortical circuit dysfunction in a mouse model of alpha-synucleinopathy in vivo.

Considerable fluctuations in cognitive performance and eventual dementia are an important characteristic of alpha-synucleinopathies, such as Parkinson's disease and Lewy Body dementia and are linked to cortical dysfunction. The presence of misfolded and aggregated alpha-synuclein in the cerebral cortex of patients has been suggested to play a crucial role in this process. However, the consequences of a-synuclein accumulation on the function of cortical networks at cellular resolution in vivo are largely unknown. Here, we induced robust a-synuclein pathology in the cerebral cortex using the striatal seeding model in wild-type mice. Nine months after a single intrastriatal injection of a-synuclein preformed fibrils, we observed profound alterations of the function of layer 2/3 cortical neurons in somatosensory cortex by in vivo two-photon calcium imaging in awake mice. We detected increased spontaneous activity levels, an enhanced response to whisking and increased synchrony. Stereological analyses revealed a reduction in glutamic acid decarboxylase 67-positive inhibitory neurons in the somatosensory cortex of mice injected with preformed fibrils. Importantly, these findings point to a disturbed excitation/inhibition balance as a relevant driver of circuit dysfunction, potentially underlying cognitive changes in alpha-synucleinopathies.

NMDA Receptor Enhances Correlation of Spontaneous Activity in Neonatal Barrel Cortex.

Correlated spontaneous activity plays critical role in the organization of neocortical circuits during development. However, cortical mechanisms regulating activity correlation are still elusive. In this study, using two-photon calcium imaging of the barrel cortex layer 4 (L4) in living neonatal mice, we found that NMDA receptors (NMDARs) in L4 neurons are important for enhancement of spontaneous activity correlation. Disruption of GluN1 (Grin1), an obligatory NMDAR subunit, in a sparse population of L4 neurons reduced activity correlation between GluN1 knock-out (GluN1KO) neuron pairs within a barrel. This reduction in activity correlation was even detected in L4 neuron pairs in neighboring barrels and most evident when either or both of neurons are located on the barrel edge. Our results provide evidence for the involvement of L4 neuron NMDARs in spatial organization of the spontaneous firing activity of L4 neurons in the neonatal barrel cortex.SIGNIFICANCE STATEMENT Precise wiring of the thalamocortical circuits is necessary for proper sensory information processing, and thalamus-derived correlated spontaneous activity is important for thalamocortical circuit formation. The molecular mechanisms involved in the correlated activity transfer from the thalamus to the neocortex are largely unknown. In vivo two-photon calcium imaging of the neonatal barrel cortex revealed that correlated spontaneous activity between layer four neurons is reduced by mosaic knock-out (KO) of the NMDA receptor (NMDAR) obligatory subunit GluN1. Our results suggest that the function of NMDARs in layer four neurons is necessary for the communication between presynaptic and postsynaptic partners during thalamocortical circuit formation.

Multiscale mapping of frequency sweep rate in mouse auditory cortex.

Functional organization is a key feature of the neocortex that often guides studies of sensory processing, development, and plasticity. Tonotopy, which arises from the transduction properties of the cochlea, is the most widely studied organizational feature in auditory cortex; however, in order to process complex sounds, cortical regions are likely specialized for higher order features. Here, motivated by the prevalence of frequency modulations in mouse ultrasonic vocalizations and aided by the use of a multiscale imaging approach, we uncover a functional organization across the extent of auditory cortex for the rate of frequency modulated (FM) sweeps. In particular, using two-photon Ca2+ imaging of layer 2/3 neurons, we identify a tone-insensitive region at the border of AI and AAF. This central sweep region behaves fundamentally differently from nearby neurons in AI and AII, responding preferentially to fast FM sweeps but not to tones or bandlimited noise. Together these findings define a second dimension of organization in the mouse auditory cortex for sweep rate complementary to that of tone frequency.