Synchronized firing of fast-spiking interneurons is critical to maintain balanced firing between direct and indirect pathway neurons of the striatum

Abstract

The inhibitory circuits of the striatum are known to be critical for motor function, yet their contributions to Parkinsonian motor deficits are not clear. Altered firing in the globus pallidus suggests that striatal medium spiny neurons (MSN) of the direct (D1 MSN) and indirect pathway (D2 MSN) are imbalanced during dopamine depletion. Both MSN classes receive inhibitory input from each other and from inhibitory interneurons within the striatum, specifically the fast-spiking interneurons (FSI). To investigate the role of inhibition in maintaining striatal balance, we developed a biologically-realistic striatal network model consisting of multicompartmental neuron models: 500 D1 MSNs, 500 D2 MSNs and 49 FSIs. The D1 and D2 MSN models are differentiated based on published experiments of individual channel modulations by dopamine, with D2 MSNs being more excitable than D1 MSNs. Despite this difference in response to current injection, in the network D1 and D2 MSNs fire at similar frequencies in response to excitatory synaptic input. Simulations further reveal that inhibition from FSIs connected by gap junctions is critical to produce balanced firing. Although gap junctions produce only a small increase in synchronization between FSIs, removing these connections resulted in significant firing differences between D1 and D2 MSNs, and balanced firing was restored by providing synchronized cortical input to the FSIs. Together these findings suggest that desynchronization of FSI firing is sufficient to alter balanced firing between D1 and D2 MSNs.

Keywords: Parkinson's disease; fast-spiking interneuron; gap junctions; medium-spiny neuron; striatum.

Fig. 1.

Differences in intrinsic channel properties are sufficient to describe the dichotomy in excitability between D1 and D2 medium spiny neurons (MSNs). A: experimental observations of responses of D1 and D2 MSNs to current injection. [Adapted with permission from Gertler et al. 2008.] A1: D1 MSNs have significantly higher rheobase current (median, 270 pA, n = 35) than D2 MSNs (median, 130 pA, n = 31). A2: frequency-current (F–I) plot of D1 and D2 MSNs demonstrate higher intrinsic excitability in D2 MSNs. B: models of D1 and D2 MSNs constructed with differences in intrinsic excitability reproduce electrophysiological dichotomy. The intrinsic channels with different properties are the L-type calcium channels, fast-sodium channels, slowly inactivating A-type (transient) potassium channel (KAs) and inward-rectifying potassium channels (KIR). B1: D1 and D2 MSN models have rheobase current of 275 pA and 155 pA, respectively. B2: F–I plot of these models reproduce experimentally observed differences in spiking activity. C: simulations suggest that models of D1 and D2 MSNs differentiated based solely on morphological differences do not replicate dichotomy in spiking activity. C1: D1 MSN models constructed with six primary dendrites and D2 MSN models constructed with four primary dendrites have rheobase currents of 210 pA and 160 pA, respectively. C2: the F–I plot of these MSN models does not replicate the dichotomy of D1 and D2 MSN excitability seen experimentally.

Fig. 2.

Model of striatal network with 1,000 MSNs and 49 fast-spiking interneurons (FSIs). A: schematic of network model with MSNs receiving inhibitory input from FSIs and other MSNs. Roughly equal numbers of D1 and D2 MSNs are randomly distributed on a regular grid. FSIs receive input from other FSIs through both GABAergic synapses and gap junction (GJ) connections. Excitatory input to both MSNs and FSIs is provided by simulated Poisson trains. B: heterogeneous distribution of MSNs was generated by changing KAs and N-methyl-d-aspartate channel conductances by ±10%. The range of responses of these D1 and D2 MSN model neurons to somatic current injection was within the range of responses seen experimentally. C: raster plots of D1 (C1) and D2 (C2) MSNs in response to synaptic input in the striatal network. D: firing frequencies of D1 and D2 MSN populations during the upstate, calculated from rasters in C by averaging across the neurons within a class and across upstates. Excitatory synaptic input (green) is illustrated to show latency of MSN firing with respect to input. Both MSN classes have similar firing frequencies (D1 MSNs: 10.77 ± 0.60 Hz; D2 MSNs: 9.59 ± 0.13 Hz). E: D1 and D2 MSNs have balanced firing frequencies across a range of cortical input frequencies.

Fig. 3.

Contribution of FSI-MSN and MSN-MSN synapses to striatal balance. A: removing FSI inhibition (F) to MSNs introduces a 40% imbalance in firing between D1 and D2 MSNs. B: removing MSN-MSN synapses (M) and replacing those GABAergic synapses with extrinsic input trains (Ext) that keep the overall inhibition similar to control (CNTL) level results in a large increase in firing frequency, but only 18% difference between D1 and D2 MSN firing frequencies. C: reducing the weight (dashed lines) of FSI-MSN synapses to the level of MSN-MSN synapses (8.4 nS to 0.75 nS) produced slight changes (9%) to firing differences between D1 and D2 MSNs. D: removing proximal FSI-MSN synapses and making FSI-MSN synapses as distal as MSN-MSN synapses also did not disrupt balance of firing. E: a delay of 65 ms was added to FSI-MSN synaptic connections to identify the contribution of early FSI firing on disrupting balance in firing. This resulted in a 10% difference in firing between the MSN classes. All percent differences are calculated as difference divided by mean. F: table of mean firing frequencies and %differences between D1 and D2 MSNs for the CNTL condition and for the conditions are represented by the respective panels.

Fig. 4.

Contributions of FSI-FSI interactions on balance of firing between D1 and D2 MSNs. A: the mean firing frequency of FSIs is minimally affected by GJ inputs from other FSIs. Removal of GJ results in slightly higher firing of the FSIs. Providing synchronous cortical input to FSIs when GJs are removed does not produce significant changes to FSI firing frequencies. B: cross-correlograms of FSIs during the same conditions as in A show that GJ removal decreases synchrony, and synchronous input restores synchrony, although not quite to the same level seen in the intact network. Note that synchrony is calculated between connected FSIs (Hjorth et al. 2009). Cross-correlogram between nonconnected FSIs reveals no synchrony (data not shown). Inset shows cross-correlograms over entire simulation period and depicts slight oscillatory behavior. C: firing frequencies of D1 and D2 MSNs when GJs between FSIs are removed. D2 MSNs fire at a significantly higher frequency compared with D1 MSNs. D: balance in firing is restored when synchronous cortical input is provided to FSIs during GJ block. E: cross-correlograms of MSNs during CNTL and no FSI conditions. In addition to leading to disruption of balance between D1 and D2 MSN firing, removing FSI results in decreased overall synchrony between MSNs. Inset shows cross-correlogram over entire simulation period.

Fig. 5.

Effects of modulating channel properties and their interaction with inhibitory input on affecting striatal balance. A: equalizing L-type calcium channels (CaL), fast-sodium channel (NaF), KAs, or KIR produces imbalance between D1 and D2 MSN firing (P < 0.01 for all conditions). B: when CaL or KAs/KIR (data not shown) conductances are equalized between D1 and D2 MSNs, removing FSIs or GJs does not affect the imbalance in firing. When NaF properties are equalized, removing GJs no longer produces the significant difference in firing between the two MSN classes, restoring balance in firing between D1 and D2 MSNs.

Fig. 6.

Summary of conditions that produce Parkinsonian imbalance and conditions that restore striatal balance. This schematic shows the nature of connections between FSI and MSNs and between MSNs, and the effect of removing these connections. When input from FSIs (black) to D1 (gray) and D2 (gray) MSNs is removed, D2 MSNs fire more than D1 MSNs. When GJs between FSIs are removed, D2 MSNs again fire at higher frequencies compared with D1 MSNs. These two cases have been labeled as Parkinsonian imbalance. In the latter case, balance is restored when the synchronicity of FSIs is increased by alternative means, such as providing highly correlated cortical input to the FSIs. Making NaF the same between D1 and D2 MSNs also restores balance during GJ block. The network output seen in the CNTL network where the connections are intact is labeled as striatal balance. Glutamatergic input to both FSIs and MSNs, along with feedback connections between MSNs, have been omitted from the schematic to highlight the effect of FSI-MSN connections on striatal balance.