RESUMO
Latrophilin-1 (Lphn1, aka CIRL1 and CL1; gene symbol Adgrl1) is an adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for α-latrotoxin. Here we analyzed conditional knock-in/knock-out mice for Lphn1 that contain an extracellular myc epitope tag. Mice of both sexes were used in all experiments. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but is required for some inhibitory synaptic connections.
Assuntos
Camundongos Knockout , Receptores de Peptídeos , Sinapses , Animais , Feminino , Masculino , Camundongos , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Hipocampo/citologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Camundongos Endogâmicos C57BL , Inibição Neural/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
The mechanisms utilized by neurons to regulate the efficacy of phasic and tonic inhibition and their impacts on synaptic plasticity and behavior are incompletely understood. Cleft lip and palate transmembrane protein 1 (Clptm1) is a membrane-spanning protein that interacts with multiple γ-aminobutyric acid type A receptor (GABAAR) subunits, trapping them in the endoplasmic reticulum and Golgi network. Overexpression and knock-down studies suggest that Clptm1 modulates GABAAR-mediated phasic inhibition and tonic inhibition as well as activity-induced inhibitory synaptic homeostasis in cultured hippocampal neurons. To investigate the role of Clptm1 in the modulation of GABAARs in vivo, we generated Clptm1 knock-out (KO) mice. Here, we show that genetic KO of Clptm1 elevated phasic and tonic inhibitory transmission in both male and female heterozygous mice. Although basal excitatory synaptic transmission was not affected, Clptm1 haploinsufficiency significantly blocked high-frequency stimulation-induced long-term potentiation (LTP) in hippocampal CA3âCA1 synapses. In the hippocampus-dependent contextual fear-conditioning behavior task, both male and female Clptm1 heterozygous KO mice exhibited impairment in contextual fear memory. In addition, LTP and contextual fear memory were rescued by application of L-655,708, a negative allosteric modulator of the extrasynaptic GABAAR α5 subunit. These results suggest that haploinsufficiency of Clptm1 contributes to cognitive deficits through altered synaptic transmission and plasticity by elevation of inhibitory neurotransmission, with tonic inhibition playing a major role.
Assuntos
Haploinsuficiência , Proteínas de Membrana , Camundongos Knockout , Plasticidade Neuronal , Receptores de GABA-A , Transmissão Sináptica , Animais , Camundongos , Masculino , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Feminino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transmissão Sináptica/fisiologia , Plasticidade Neuronal/fisiologia , Plasticidade Neuronal/genética , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Potenciação de Longa Duração/genética , Hipocampo/metabolismo , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Medo/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Memória/fisiologia , Inibição Neural/fisiologiaRESUMO
Transspinal (or transcutaneous spinal cord) stimulation is a noninvasive, cost-effective, easily applied method with great potential as a therapeutic modality for recovering somatic and nonsomatic functions in upper motor neuron disorders. However, how transspinal stimulation affects motor neuron depolarization is poorly understood, limiting the development of effective transspinal stimulation protocols for rehabilitation. In this study, we characterized the responses of soleus α motor neurons to single-pulse transspinal stimulation using single-motor unit (SMU) discharges as a proxy given the 1:1 discharge activation between the motor neuron and the motor unit. Peristimulus time histogram, peristimulus frequencygram, and surface electromyography (sEMG) were used to characterize the postsynaptic potentials of soleus motor neurons. Transspinal stimulation produced short-latency excitatory postsynaptic potentials (EPSPs) followed by two distinct phases of inhibitory postsynaptic potentials (IPSPs) in most soleus motor neurons and only IPSPs in others. Transspinal stimulation generated double discharges at short interspike intervals in a few motor units. The short-latency EPSPs were likely mediated by muscle spindle group Ia and II afferents, and the IPSPs via excitation of group Ib afferents and recurrent collaterals of motor neurons leading to activation of diverse spinal inhibitory interneuronal circuits. Further studies are warranted to understand better how transspinal stimulation affects depolarization of α motor neurons over multiple spinal segments. This knowledge will be seminal for developing effective transspinal stimulation protocols in upper motor neuron lesions.NEW & NOTEWORTHY Transspinal stimulation produces distinct actions on soleus motor neurons: an early short-latency excitation followed by two inhibitions or only inhibition and doublets. These results show how transspinal stimulation affects depolarization of soleus α motor neurons in healthy humans.
Assuntos
Neurônios Motores , Músculo Esquelético , Humanos , Neurônios Motores/fisiologia , Masculino , Adulto , Músculo Esquelético/fisiologia , Feminino , Potenciais Pós-Sinápticos Excitadores/fisiologia , Estimulação da Medula Espinal/métodos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Eletromiografia , Adulto Jovem , Medula Espinal/fisiologiaRESUMO
Two subtypes of striatal spiny projection neurons, iSPNs and dSPNs, whose axons form the "indirect" and "direct" pathways of the basal ganglia, respectively, both make synaptic connections in the external globus pallidus (GPe) but are usually found to have different effects on behavior. Activation of the terminal fields of iSPNs or dSPNs generated compound currents in almost all GPe neurons. To determine whether iSPNs and dSPNs have the same or different effects on pallidal neurons, we studied the unitary synaptic currents generated in GPe neurons by action potentials in single striatal neurons. We used optogenetic excitation to elicit repetitive firing in a small number of nearby SPNs, producing sparse barrages of inhibitory postsynaptic currents (IPSCs) in GPe neurons. From these barrages, we isolated sequences of IPSCs with similar time courses and amplitudes, which presumably arose from the same SPN. There was no difference between the amplitudes of unitary IPSCs generated by the indirect and direct pathways. Most unitary IPSCs were small, but a subset from each pathway were much larger. To determine the effects of these unitary synaptic currents on the action potential firing of GPe neurons, we drove SPNs to fire as before and recorded the membrane potential of GPe neurons. Large unitary potentials from iSPNs and dSPNs perturbed the spike timing of GPe neurons in a similar way. Most SPN-GPe neuron pairs are weakly connected, but a subset of pairs in both pathways are strongly connected.NEW & NOTEWORTHY This is the first study to record the synaptic currents generated by single identified direct or indirect pathway striatal neurons on single pallidal neurons. Each GPe neuron receives synaptic inputs from both pathways. Most striatal neurons generate small synaptic currents that become influential when occurring together, but a few are powerful enough to be individually influential.
Assuntos
Potenciais Pós-Sinápticos Inibidores , Neurônios , Optogenética , Animais , Camundongos , Neurônios/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Corpo Estriado/fisiologia , Corpo Estriado/citologia , Globo Pálido/fisiologia , Globo Pálido/citologia , Potenciais de Ação/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Feminino , Vias Neurais/fisiologia , Sinapses/fisiologiaRESUMO
Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions.NEW & NOTEWORTHY Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions.
Assuntos
Dopamina , Receptores de GABA-A , Células Ganglionares da Retina , Animais , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Dopamina/metabolismo , Dopamina/farmacologia , Receptores de GABA-A/metabolismo , Camundongos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Receptores Opioides mu/metabolismo , Masculino , Potenciais Pós-Sinápticos Inibidores/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Feminino , Agonistas de Dopamina/farmacologiaRESUMO
Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTDs). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole cell patch-clamp recording. Acute MeHg exposure (20 µM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) charges were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPA receptor- nor NMDA receptor-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired-pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.NEW & NOTEWORTHY Prefrontal cortical neurons are highly susceptible to glutamatergic excitotoxicity associated with neuronal degeneration in frontal dementia and to environmental toxicant exposure, one potential contributor to FTD. However, this has not been systematically studied. Our results demonstrate that methylmercury exposure leads to hyperexcitability of prefrontal cortical neurons by shifting excitatory to inhibitory (E-I) balance and raising sensitivity for spiking. Our results provide a mechanism by which environmental neurotoxicants may contribute to pathogenesis of diseases such as FTD.
Assuntos
Potenciais Pós-Sinápticos Excitadores , Compostos de Metilmercúrio , Córtex Pré-Frontal , Células Piramidais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Animais , Compostos de Metilmercúrio/toxicidade , Masculino , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ratos , Ratos Sprague-Dawley , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologiaRESUMO
The infralimbic cortex (IL) is part of the medial prefrontal cortex (mPFC), exerting top-down control over structures that are critically involved in the development of alcohol use disorder (AUD). Activity of the IL is tightly controlled by γ-aminobutyric acid (GABA) transmission, which is susceptible to chronic alcohol exposure and withdrawal. This inhibitory control is regulated by various neuromodulators, including 5-hydroxytryptamine (5-HT; serotonin). We used chronic intermittent ethanol vapor inhalation exposure, a model of AUD, in male Sprague-Dawley rats to induce alcohol dependence (Dep) followed by protracted withdrawal (WD; 2 weeks) and performed ex vivo electrophysiology using whole-cell patch clamp to study GABAergic transmission in layer V of IL pyramidal neurons. We found that WD increased frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs), whereas miniature IPSCs (mIPSCs; recorded in the presence of tetrodotoxin) were unaffected by either Dep or WD. The application of 5-HT (50 µM) increased sIPSC frequencies and amplitudes in naive and Dep rats but reduced sIPSC frequencies in WD rats. Additionally, 5-HT2A receptor antagonist M100907 and 5-HT2C receptor antagonist SB242084 reduced basal GABA release in all groups to a similar extent. The blockage of either 5-HT2A or 5-HT2C receptors in WD rats restored the impaired response to 5-HT, which then resembled responses in naive rats. Our findings expand our understanding of synaptic inhibition in the IL in AUD, indicating that antagonism of 5-HT2A and 5-HT2C receptors may restore GABAergic control over IL pyramidal neurons. SIGNIFICANCE STATEMENT: Impairment in the serotonergic modulation of GABAergic inhibition in the medial prefrontal cortex contributes to alcohol use disorder (AUD). We used a well-established rat model of AUD and ex vivo whole-cell patch-clamp electrophysiology to characterize the serotonin modulation of GABAergic transmission in layer V infralimbic (IL) pyramidal neurons in ethanol-naive, ethanol-dependent (Dep), and ethanol-withdrawn (WD) male rats. We found increased basal inhibition following WD from chronic alcohol and altered serotonin modulation. Exogenous serotonin enhanced GABAergic transmission in naive and Dep rats but reduced it in WD rats. 5-HT2A and 5-HT2C receptor blockage in WD rats restored the typical serotonin-mediated enhancement of GABAergic inhibition. Our findings expand our understanding of synaptic inhibition in the infralimbic neurons in AUD.
Assuntos
Alcoolismo , Etanol , Potenciais Pós-Sinápticos Inibidores , Córtex Pré-Frontal , Ratos Sprague-Dawley , Serotonina , Síndrome de Abstinência a Substâncias , Transmissão Sináptica , Ácido gama-Aminobutírico , Animais , Masculino , Serotonina/metabolismo , Ratos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Alcoolismo/metabolismo , Alcoolismo/fisiopatologia , Etanol/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Ácido gama-Aminobutírico/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismoRESUMO
Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17ß-estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein-coupled estrogen receptor-1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long-Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor-mediated excitatory synaptic currents. However, GABA receptor-mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20-min washout period. The inhibition of GABA-mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2-induced reduction in IPSCs. GPER1 can also stimulate extracellular signal-regulated kinase (ERK), a negative modulator of GABAA receptors, and blocking activation of ERK with PD90859 prevented the E2-induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling-mediated reduction in GABA-mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK-dependent alterations in synaptic transmission in other brain areas.
Assuntos
Córtex Entorrinal , Estradiol , MAP Quinases Reguladas por Sinal Extracelular , Neurônios , Ratos Long-Evans , Receptores Acoplados a Proteínas G , Animais , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Estradiol/farmacologia , Feminino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Receptores de Estrogênio/metabolismo , Ovariectomia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Patch-Clamp , Estrogênios/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidoresRESUMO
Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus and ventral pallidum afferents. We next determined the phase resetting curve, the reversal potential for GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs), and the average interspike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the interspike interval or phase. Simulations were performed to predict the pause duration resulting from the synchronous arrival of multiple uIPSGs and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns, including pauses that have been implicated in reinforcement.
Assuntos
Potenciais de Ação , Neurônios Dopaminérgicos , Potenciais Pós-Sinápticos Inibidores , Inibição Neural , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/fisiologia , Neurônios Dopaminérgicos/fisiologia , Masculino , Feminino , Potenciais Pós-Sinápticos Inibidores/fisiologia , Inibição Neural/fisiologia , Potenciais de Ação/fisiologia , Modelos Neurológicos , Camundongos Endogâmicos C57BL , Camundongos , Estimulação ElétricaRESUMO
Whisker stimulation in awake mice evokes transient suppression of simple spike probability in crus I/II Purkinje cells. Here, we investigated how simple spike suppression arises synaptically, what it encodes, and how it affects cerebellar output. In vitro, monosynaptic parallel fiber (PF)-excitatory postsynaptic currents (EPSCs) facilitated strongly, whereas disynaptic inhibitory postsynaptic currents (IPSCs) remained stable, maximizing relative inhibitory strength at the onset of PF activity. Short-term plasticity thus favors the inhibition of Purkinje spikes before PFs facilitate. In vivo, whisker stimulation evoked a 2-6 ms synchronous spike suppression, just 6-8 ms (â¼4 synaptic delays) after sensory onset, whereas active whisker movements elicited broadly timed spike rate increases that did not modulate sensory-evoked suppression. Firing in the cerebellar nuclei (CbN) inversely correlated with disinhibition from sensory-evoked simple spike suppressions but was decoupled from slow, non-synchronous movement-associated elevations of Purkinje firing rates. Synchrony thus allows the CbN to high-pass filter Purkinje inputs, facilitating sensory-evoked cerebellar outputs that can drive movements.
Assuntos
Potenciais de Ação , Núcleos Cerebelares , Células de Purkinje , Sinapses , Animais , Células de Purkinje/fisiologia , Núcleos Cerebelares/fisiologia , Núcleos Cerebelares/citologia , Camundongos , Potenciais de Ação/fisiologia , Sinapses/fisiologia , Vibrissas/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos Inibidores/fisiologia , MasculinoRESUMO
Elevated intraocular pressure (IOP) triggers glaucoma by damaging the output neurons of the retina called retinal ganglion cells (RGCs). This leads to the loss of RGC signaling to visual centers of the brain such as the dorsolateral geniculate nucleus (dLGN), which is critical for processing and relaying information to the cortex for conscious vision. In response to altered levels of activity or synaptic input, neurons can homeostatically modulate postsynaptic neurotransmitter receptor numbers, allowing them to scale their synaptic responses to stabilize spike output. While prior work has indicated unaltered glutamate receptor properties in the glaucomatous dLGN, it is unknown whether glaucoma impacts dLGN inhibition. Here, using DBA/2J mice, which develop elevated IOP beginning at 6-7â months of age, we tested whether the strength of inhibitory synapses on dLGN thalamocortical relay neurons is altered in response to the disease state. We found an enhancement of feedforward disynaptic inhibition arising from local interneurons along with increased amplitude of quantal inhibitory synaptic currents. A combination of immunofluorescence staining for the γ-aminobutyric acid (GABA)A-α1 receptor subunit, peak-scaled nonstationary fluctuation analysis, and measures of homeostatic synaptic scaling pointed to an â¼1.4-fold increase in GABA receptors at postsynaptic inhibitory synapses, although several pieces of evidence indicate a nonuniform scaling across inhibitory synapses within individual relay neurons. Together, these results indicate an increase in inhibitory synaptic strength in the glaucomatous dLGN, potentially pointing toward homeostatic compensation for disruptions in network and neuronal function triggered by increased IOP.