Biology subjects

Khondaker, R.

Publications and source records attributed to Khondaker, R..

3 recordsLinked to original sources

bioRxiv2026

Input-and cell-type-specific developmental alterations to thalamic synapses in a Dravet syndrome mouse model

Dravet syndrome is an epileptic encephalopathy most often caused by loss-of-function mutations in the SCN1A gene, leading to haploinsufficiency of the voltage-gated sodium channel NaV1.1. Seizures begin during infancy and generally wane throughout childhood, but behavioral symptoms, such as intellectual disability, motor impairments, and autistic features, remain through adulthood. Seizures primarily stem from inhibitory neuron hypo-excitability in the cortex, hippocampus, and thalamus, but circuit abnormalities underlying persistent behavioral symptoms are poorly understood. Prior work showed synapse dysfunction in thalamocortical neurons in four-week-old DS mice. To understand when synaptic deficits develop and whether they could contribute to persistent thalamic dysfunction, we investigated synapse function in the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus prior to seizure onset (P13-P17), after the period of highest seizure burden (P28-P32), and in adulthood (P58-P63). Recordings of VPL and VPM synaptic activity showed excitatory input to the VPL was significantly reduced after seizure onset and this reduction persisted through adulthood, while VPM excitatory input was unaffected. We further showed a selective reduction in the function and number of excitatory sensory synapses in the VPL, with no change to cortical synapses. VPL and VPM neurons both showed inhibitory synapse dysfunction at four weeks, which persisted into adult DS mice only in VPL neurons. These results revealed persistent input- and cell-type-specific alterations to thalamic synapses that develop after seizure onset and are maintained into adulthood, suggesting that synaptic deficits could contribute to ongoing circuit dysfunction in DS.

neuroscience↗

bioRxiv2024

Input-specific localization of NMDA receptor GluN2 subunits in thalamocortical neurons

Molecular and functional diversity among synapses is generated, in part, by differential expression of neurotransmitter receptors and their associated protein complexes. N-methyl-D-aspartate receptors (NMDARs) are tetrameric ionotropic glutamate receptors that most often comprise two GluN1 and two GluN2 subunits. NMDARs generate functionally diverse synapses across neuron populations through cell-type-specific expression patterns of GluN2 subunits (GluN2A - 2D), which have vastly different functional properties and distinct downstream signaling. Diverse NMDAR function has also been observed at anatomically distinct inputs to a single neuron population. However, the mechanisms that generate input-specific NMDAR function remain unknown as few studies have investigated subcellular GluN2 subunit localization in native brain tissue. We investigated NMDAR synaptic localization in thalamocortical (TC) neurons expressing all four GluN2 subunits. Utilizing super resolution imaging and knockout-validated antibodies, we revealed subtype- and input-specific GluN2 localization at corticothalamic (CT) versus sensory inputs to TC neurons in 4-week-old male and female C57Bl/6J mice. GluN2B was the most abundant postsynaptic subunit across all glutamatergic synapses followed by GluN2A and GluN2C, and GluN2D was localized to the fewest synapses. GluN2B was preferentially localized to CT synapses over sensory synapses, while GluN2A and GluN2C were more abundant at sensory inputs compared to CT inputs. Furthermore, postsynaptic scaffolding proteins PSD95 and SAP102 were preferentially localized with specific GluN2 subunits, and SAP102 was more abundant at sensory synapses than PSD95. This work indicates that TC neurons exhibit subtype- and input-specific localization of diverse NMDARs and associated scaffolding proteins that likely contribute to functional differences between CT and sensory synapses. HIGHLIGHTSO_LINMDAR subtypes and synaptic scaffolding proteins show preferential localization at specific inputs to thalamocortical neurons. C_LIO_LIGluN2B was preferentially localized to corticothalamic synapses, while GluN2A and GluN2C were more abundant at sensory inputs to thalamocortical neurons. C_LIO_LIColocalization between synaptic scaffolding proteins with NMDARs was GluN2 subtype-dependent. C_LIO_LINMDAR subsynaptic organization in thalamocortical neurons is input- and GluN2-subtype specific. C_LI

neuroscience↗

bioRxiv2022

Ventral posterolateral and ventral posteromedial thalamus neurons have distinct synaptic and cellular physiology

Somatosensory information is propagated from the periphery to the cerebral cortex by two parallel pathways through the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus. VPL and VPM neurons receive somatosensory signals from the body and head, respectively. VPL and VPM neurons also receive cell-type-specific GABAergic input from the reticular nucleus of the thalamus (nRT). Although VPL and VPM neurons have distinct connectivity and physiological roles, differences in the functional properties of VPL and VPM neurons remain unclear as they are often studied as one ventrobasal (VB) thalamus neuron population. Here, we directly compared synaptic and intrinsic properties of VPL and VPM neurons in C57Bl/6J mice of both sexes aged P25-P32. Recordings of spontaneous synaptic transmission suggested that VPL neurons receive excitatory synaptic input with higher frequency and strength than VPM neurons, while VPL neurons exhibited weaker inhibitory synapse strength than VPM neurons. Furthermore, VPL neurons showed enhanced depolarization-induced spike firing and greater spike frequency adaptation than VPM neurons. VPL and VPM neurons fired similar numbers of spikes during hyperpolarization rebound bursts, but VPM neurons exhibited shorter burst latency compared to VPL neurons, which correlated with increased sag potential during hyperpolarization. This work indicates that VPL and VPM thalamocortical neurons are functionally distinct populations. The observed functional differences could have important implications for their specific physiological and pathophysiological roles within the somatosensory thalamocortical network.

neuroscience↗